-Cell CaV channel regulation in physiology and pathophysiology
Shao-Nian Yang and
Per-Olof Berggren
The Rolf Luft Center for Diabetes Research, Karolinska Diabetes Center, Department of Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Submitted 29 January 2004
; accepted in final form 17 September 2004
 |
ABSTRACT
|
---|
The
-cell is equipped with at least six voltage-gated Ca2+ (CaV) channel
1-subunits designated CaV1.2, CaV1.3, CaV2.1, CaV2.2, CaV2.3, and CaV3.1. These principal subunits, together with certain auxiliary subunits, assemble into different types of CaV channels conducting L-, P/Q-, N-, R-, and T-type Ca2+ currents, respectively. The
-cell shares customary mechanisms of CaV channel regulation with other excitable cells, such as protein phosphorylation, Ca2+-dependent inactivation, and G protein modulation. However, the
-cell displays some characteristic features to bring these mechanisms into play. In islet
-cells, CaV channels can be highly phosphorylated under basal conditions and thus marginally respond to further phosphorylation. In
-cell lines, CaV channels can be surrounded by tonically activated protein phosphatases dominating over protein kinases; thus their activity is dramatically enhanced by inhibition of protein phosphatases. During the last 10 years, we have revealed some novel mechanisms of
-cell CaV channel regulation under physiological and pathophysiological conditions, including the involvement of exocytotic proteins, inositol hexakisphosphate, and type 1 diabetic serum. This minireview highlights characteristic features of customary mechanisms of CaV channel regulation in
-cells and also reviews our studies on newly identified mechanisms of
-cell CaV channel regulation.
exocytotic proteins; inositol hexakisphosphate; pancreatic
-cell; type 1 diabetic serum; voltage-gated Ca2+ channels
THE PATCH CLAMP TECHNIQUE endows electrophysiologists with great possibilities to investigate voltage-gated Ca2+ (CaV) channels and their regulation at the molecular level, especially in small cells like the pancreatic
-cell (32). Single CaV channels were discovered in Helix pomatia neurons shortly after the development of this powerful technique (61). Subsequently, different groups made successful recordings of both single and whole cell CaV channel currents in the pancreatic
-cells (5). The biophysical properties, subcellular distributions, and functions of CaV channels have been extensively examined by combining the techniques of electrophysiology, molecular biology, and microscopy. Functional CaV channels are Ca2+-conducting pores primarily localized in the plasma membrane (15). In response to membrane depolarization, the conformation of CaV channels switches from a closed state to an open state. Ca2+ influx through CaV channels serves as the second messenger to couple electrical signaling to chemical signaling (15). It controls a diverse range of intracellular events, including exocytosis, endocytosis, muscle contraction, synaptic transmission, and metabolism (15). It triggers life at fertilization and controls proliferation, differentiation, and development through the regulation of protein phosphorylation, gene expression, and cell cycle (10). It causes cell death through initiation of apoptosis and necrosis (10, 11).
A mission of paramount importance for
-cell CaV channels is to trigger insulin exocytosis. When plasma glucose levels rise, resultant increases in glucose uptake into and metabolism by the pancreatic
-cell lead to an increase in the ATP-to-ADP ratio, inhibiting
-cell ATP-sensitive K+ channels and consequently depolarization of the plasma membrane. The membrane depolarization opens
-cell CaV channels to mediate Ca2+ influx, thereby stimulating insulin secretion (9).
-Cell CaV channel activity and/or density is regulated by a variety of mechanisms, such as cytoplasmic free Ca2+ concentration ([Ca2+]i), protein phosphorylation, translocation, interaction with other proteins, and so on. Up- and downregulation of CaV channel activity and/or density result in more or less insulin exocytosis, respectively (1, 4, 41, 47, 51, 75, 79, 113, 116). Another important task of
-cell CaV channels is to regulate
-cell fate by controlling [Ca2+]i dynamics (48, 49). Hyperactivation of
-cell CaV channels leads to
-cell death (48, 49). Recently, novel mechanisms of
-cell CaV channel regulation have been revealed under physiological and pathological conditions. In this review, we will briefly summarize current views on the biophysical feature, structure, and function of
-cell CaV channels. We will then highlight and discuss recent findings concerning molecular mechanisms of
-cell CaV channel regulation.
Electrophysiological recording, pharmacological manipulation, biochemical purification, and molecular cloning have identified diverse CaV currents, CaV channel proteins, and genes. The researchers in these different fields used to employ different terminologies to describe these entities (25). Physiologists depicted CaV currents phenomenologically (such as long lasting and large conductance for L-type CaV currents). Biochemists named CaV channel proteins with Greek letters (
1-,
-,
-, and
2
-subunits). Molecular biologists described CaV channel mRNAs using the terminology class A, class B, etc. This made the nomenclature of CaV channels confusing. Therefore, a comprehensive nomenclature of CaV channels was proposed in 2000 on the basis of sequence analysis (25). It classifies CaV channels into three families CaV1, CaV2, and CaV3, consisting of closely related members. This nomenclature, known as the structural nomenclature, has been widely accepted to describe CaV channel proteins and mRNAs. However, it is hardly applied to the description of CaV currents recorded from native cells expressing complex mixtures of CaV channel subunits. In this review, the phenomenological nomenclature is used to describe CaV currents, and the structural nomenclature is used to describe CaV channel proteins and mRNAs. To comprehend the literature cited, some old terms are mentioned and followed by the structural nomenclature in brackets.
 |
PHYSIOLOGICAL TYPES OF CAV CHANNELS
|
---|
Our understanding of the diversity of CaV channels began with electrophysiological recordings. In 1975, Hagiwara et al. (30) recorded two types of CaV currents with distinct activation and inactivation from fertilized starfish eggs. They made the earliest classification of CaV channels, channel I (low-voltage activated, LVA) and channel II (high-voltage activated, HVA), on the basis of biophysical properties. Six years later, the LVA and HVA Ca2+ currents were also found in central neurons (60). Application of the patch clamp technique in combination with selective CaV channel blockers has been crucial in the further classification of CaV channels. The Tsien group has made a number of landmark studies on CaV channel classification using patch clamp analysis in combination with pharmacological manipulation. This group and others (59, 81, 104) identified five or six types of CaV currents, L-, P/Q-, N-, R-, and T-types, and proposed the presence of the corresponding types of CaV channels. The biophysical and pharmacological properties as well as localizations and functions of CaV channels are summarized in Table 1.
T-type CaV channels need a small depolarization to become activated, thus designated LVA Ca2+ channels. The name T-type CaV channels was derived from their biophysical properties, i.e., a tiny single-channel conductance and a transient kinetics of inactivation. T-type CaV channels have been identified in neurons, muscles, endocrine cells, and even nonexcitable cells. They are mainly involved in repetitive firing in excitable cells (15, 104).
The L-, P/Q-, N-, and R-type CaV channels are opened by large depolarizations and belong to the HVA Ca2+ channel family. Its members can be discriminated according to their biophysical and pharmacological properties. L-type CaV channels are sensitive to dihydropyridines (DHPs), are characterized by a large unitary conductance, and conduct a long-lasting current. Therefore, these channels are named L-type CaV channels. This type of CaV channel is widely distributed in all excitable and some nonexcitable cells. They play important roles in excitation-contraction coupling, hormone secretion, [Ca2+]i homeostasis, and gene regulation (15, 104).
N-type CaV channels display some biophysical properties, such as single-channel conductance and inactivation rate, intermediate between those of the T- and L-type CaV channels. These channels are neither T nor L and are blocked by
-conotoxin GVIA. Originally they were found only in neurons and play a key role in neurotransmitter release. Accordingly, they are termed N-type CaV channels (15, 104).
P-type CaV channels were first identified in cerebellar Purkinje cells (59). Subsequently, Q-type CaV channels were discovered in cerebellar granule cells (81). Initially, the P- and Q-types were regarded as two distinct types on the basis of differences in their inactivation rate and sensitivity to
-agatoxin IVA. These two types are now combined as P/Q-type CaV channels because both of them use the same principal subunit, CaV2.1, to conduct currents. The biophysical properties and functions of P/Q-type CaV channels highly overlap with those of N-type CaV channels (15, 104).
R-type CaV channels were found in the same experiment where Q-type CaV channels were characterized (81). In cerebellar granule cells, a residual CaV current was shown to be resistant to DHPs and N- and P/Q-type CaV channel toxins. A novel toxin, SNX-482, with high affinity for R-type CaV channels has been purified (71). Fast inactivation is a major biophysical difference between R-type and other HVA Ca2+ channels. The R-type CaV channel is a key player in generation of Ca2+-dependent action potentials and plays a role in neurotransmitter release (15, 104).
 |
MOLECULAR STRUCTURE OF CAv CHANNEL SUBUNITS
|
---|
Advanced molecular biology, protein chemistry, and X-ray crystallography enabled us to learn a great deal about CaV channels. The Catterall group (18) made the first solubilization and purification of CaV channel proteins from the transverse tubule membranes of skeletal muscle. Initially, they found that the skeletal muscle CaV channel consists of
1-,
-, and
-subunits and later revealed an additional
2
-subunit (15). The Numa group (103) subsequently cloned the skeletal muscle
1S-subunit (CaV1.1) cDNA, which is the first cloned cDNA of CaV channels. Two years later, this group isolated the complete cDNA clone of the
1C-subunit (CaV1.2) from rabbit cardiac muscle and succeeded in functional expression of CaV1.2 channels in Xenopus oocytes (66). Shortly thereafter, the cDNA of the
1D-subunit (CaV1.3) was isolated from human pancreatic islets (95). Recently, the cDNA and amino acid sequences of
1G (CaV3.1) from the insulin-secreting cell line INS-1 have been determined (119). Until now, the primary structures of ten distinct
1 and numerous auxiliary subunits have been identified by cDNA cloning and sequencing (Fig. 1) (3, 15, 25).

View larger version (48K):
[in this window]
[in a new window]
|
Fig. 1. A: molecular organization of voltage-gated Ca2+ (CaV) channel subunits in the plasma membrane. B: predicted topology of CaV channel subunits. C: nomenclature of CaV channel subunits.
|
|
A model of the molecular organization of the CaV channel composed of five subunits has been derived on the basis of analysis of the biochemical properties, glycosylation, and hydrophobicity of these subunits. Basically, this model depicts that a principal transmembrane
1-subunit associates with a disulfide-linked
2
-dimer, an intracellular phosphorylated
-subunit, and a transmembrane
-subunit (15). Structure-function analysis demonstrates that the
1-subunit is the principal subunit in the channel protein complex. This subunit is equipped with a transmembrane topology of four homologous repeats (I to IV), each containing six transmembrane segments (S1 to S6) and a membrane-associated loop between transmembrane segments S5 and S6. This structure endows the
1-subunit with a Ca2+-conducting pore. The S4 segments serve as the voltage sensors for channel activation. The S5 and S6 segments as well as the membrane-associated loop between them form the pore lining of CaV channels (Fig. 1) (15). Electron microscopy-based image analysis has revealed the three-dimensional structures of CaV1.1 and CaV1.2 channels and proposed the subunit organization of these CaV channels (110, 111). In this year (2004), exciting progress has been made in understanding the CaV channel structure at the atomic level (17, 73, 107). High-resolution crystal structures reveal the following important aspects: 1) the
-subunit core contains two interacting domains, a Src homology 3 (SH3) domain and a guanylate kinase (GK) domain; 2) the
-interaction domain (AID) of
1-subunits binds to a hydrophobic cleft (
-binding pocket, ABP) but not to the previously proposed
-interaction domain (BID) of
-subunits; 3) the
-subunit may directly modulate the movement of S6 in the
1-subunit domain I to influence channel pore gating; 4) the BID preserves the structural integrity of the SH3 and GK domains and links these two domains together; and 5) the multifunctional module-containing
-subunit can perform a diverse range of tasks (17, 73, 107).
-Subunits and other subunits are not directly involved in the formation of the Ca2+-conducting pore and thus are called auxiliary subunits. However, they do play important roles in the regulation of surface expression, gating properties, and voltage dependence of CaV channels (3, 15). Four distinct
-subunits have been identified. The
-subunit is entirely cytosolic and associates with the
1-subunit. Importantly, this subunit is a substrate of protein kinase A. Modulation of CaV channel activity can result from
-subunit phosphorylation. The
-subunit has two major functions, i.e., enhancement of plasma membrane trafficking of the
1-subunit and regulation of biophysical properties of CaV channels. However, distinct
-subunits can exhibit opposite effects, especially on inactivation kinetics. For example, coexpression of the
2-subunit makes inactivation slower. On the contrary, coexpression of the
3-subunit significantly accelerates inactivation (3, 42). Molecular cloning has revealed four distinct
2
-subunits (
2
1
2
4) (3). The
2
-subunit comes from the same gene and is a two-peptide dimer linked by disulfide bounds (3). Although
2 is entirely extracellular and
possesses a single transmembrane region,
2 interacts with the
1-subunit (3). Distinct
2
-subunits have slightly different contributions to channel function (3). Basically, coexpression of the
2
-subunits promotes
1-subunit trafficking to the plasma membrane and increases current amplitude. In addition, channel activation and inactivation are also affected by the co-expression of some
2
-subunits (3). Some of these effects occur in the presence of the
-subunit, whereas others do not require the co-expression of the
-subunit (3). The
-subunit was originally identified only in skeletal muscle. Recently, several
-subunits (
1
8) have been found within a wide variety of tissues (3). All the identified
-subunits have no effect on channel trafficking (3); however, they inhibit channel activity and modulate activation and inactivation kinetics (Fig. 1) (3).
-Cell CaV channels are heterogeneous. Multiple
1-subunit mRNAs and proteins have been revealed in insulin-secreting cells or islets (Table 2). All studies indicate that the CaV1.2, and in particular CaV1.3, subunit mRNAs and proteins are predominant in all tested insulin-secreting cells and islets (36, 46, 86, 93, 95, 116). The
-cell from any tested species carries CaV1.2 and CaV1.3 subunit mRNAs (Table 2). The CaV1.2 subunit protein has been identified in mouse islet
-cells as well as in HIT-15T, RINm5F, MIN6, and
TC-3 cells (Table 2). The CaV1.3 subunit protein has been detected in mouse islet
-cells and in INS-1 and RINm5F cells (Table 2). More interestingly, expansion of the ATG trinucleotide repeat in the human CaV1.3 gene (CACNL1A2) from seven to eight was found only in type 2 diabetics. Although the frequency of this mutation is low and not associated with the development of common type 2 diabetes, it may be involved in the pathogenesis of a subgroup of this polygenic disease (114, 115). A Japanese family with spinocerebellar ataxia type 6 caused by mutations of the CaV2.1 gene (CACNL1A4) is highly associated with type 2 diabetes (100). For the rest of the
1-subunits, there are obvious interspecies differences (Table 2).
1-Subunit mRNAs and proteins in islet
-cells and insulin-secreting cell lines from different species are listed in Table 2. The
2
2-subunit mRNA has been revealed in the human pancreas (26). The
2- and
3-subunit mRNAs have been found in rat pancreatic islets. Competitive RT-PCR shows that the
2-subunit mRNA level is much higher than the
3-subunit mRNA level, suggesting that the
2-subunit is predominant in rat pancreatic islets (45). We have revealed both
2- and
3-subunits at the mRNA and protein levels in mouse islets (Berggren P-O, unpublished observations). It is unknown whether the
-subunit is expressed in the
-cell. Although some
-cell CaV channel mRNA and protein isoforms were identified using fluorescence-activated cell sorting and immunocytochemical approaches, others were manifested in islet tissues. Therefore, caution is needed in interpretation of the results from the islet tissue, as it contains four types of endocrine cells as well as nerve endings and capillaries. Application of optical tweezers, fluorescence-activated cell sorting, and single-cell PCR will provide more detailed information on
-cell CaV channel mRNA and protein isoforms.
 |
-CELL CAV CHANNELS AND INSULIN SECRETION
|
---|
Pancreatic
-cells as paraneurons are equipped with neuronal protein assemblies such as a similar set of exocytotic proteins and a rich assortment of CaV channels, including L-, P/Q-, N-, R-, and T-types (Table 2). Patch clamp studies have been extensively performed for the characterization of
-cell CaV channels. Whole cell CaV currents were first reported in the cultured neonatal rat pancreatic
-cell (90). Soon they were identified in a variety of
-cells, including insulin-secreting cell lines and islet
-cells from different species (Table 2) (5). All types of
-cell CaV channels are involved in stimulus-secretion coupling.
Physiological and pharmacological studies have revealed that the L-type CaV channel is expressed in all the islet
-cells and insulin-secreting cell lines from any species tested (Table 2). The
-cell L-type CaV channel has the same biophysical features as the neuronal L-type CaV channel: normally large single-channel conductance, long-lasting kinetics, and high sensitivity to DHPs. There is now consensus that the L-type CaV channel is the major CaV channel type playing a predominant role over other types of CaV channels in Ca2+-triggered insulin exocytosis (5, 89, 96). However, the proportion of L-type CaV currents to total CaV currents in the
-cell varies among species. The majority of CaV currents in the mouse islet
-cell flow through the L-type CaV channel. Therefore, the mouse pancreatic
-cell was thought to be equipped with only L-type CaV channels (5). However, later studies revealed the presence of other types of CaV channels as well in the mouse pancreatic
-cell (94). Also in the rat islet
-cell, the L-type CaV channel dominates, although this cell carries more types of CaV channels than the mouse
-cell (Table 2). A smaller number of CaV channel studies have been performed in human
-cells. However, data available clearly demonstrate that L-type CaV channels underlie the principal HVA Ca2+ currents of human
-cells (96). Pharmacological experiments demonstrate that 6080% of glucose-induced insulin secretion from mouse, rat, and human
-cells, equipped with various types of CaV channels, is attributed to Ca2+ influx through the L-type CaV channel (19, 72, 94). Hence, although insulin-secreting cell lines use various types of CaV channels to trigger insulin exocytosis, L-type CaV channels still play a major role (89, 91, 96, 105).
There are two subtypes of
-cell L-type CaV channels: CaV1.2 and CaV1.3 channels (69, 94, 113, 116). The distinct contribution of CaV1.2 and CaV1.3 subtypes to insulin exocytosis has not been thoroughly studied in different species and remains controversial. L-type CaV channel subtype-specific regulation of insulin secretion has not been examined in human islet
-cells. In rat
-cells, the level of
1D-subunit mRNA is 2.5 times higher than that of
1C-subunit mRNA (46). Recently,
-cell CaV1.2-specific knockout mice have been created. Mouse
-cells lacking CaV1.2 subunit exhibit a decrease in CaV currents by
45%, an inhibition of first-phase insulin secretion by
80%, and glucose intolerance (94). L-type CaV channel blockers had no effect on CaV channel currents and insulin release from
-cells lacking CaV1.2 subunits. Furthermore, previous studies showed negative CaV1.3 subunit-like immunoreactivity in mouse pancreatic
-cells (7, 94). Those results led to the conclusion that only CaV1.2 subunits conduct L-type CaV currents in mouse pancreatic
-cells and play a crucial role in stimulus-secretion coupling. However, the presence of CaV1.3 subunit mRNAs and proteins in mouse pancreatic
-cells has been clearly demonstrated by other groups (69, 116). Additionally, CaV1.3 subunit knockout mice displayed the compensatory overexpression of CaV1.2 subunit proteins in
-cells (69). Electrophysiological analysis showed that there was no difference in either total voltage-gated Ba2+ current density or L-type current density between mutant and control cells. However, biophysical properties of L-type CaV currents in CaV1.3 subunit-deficient
-cells were significantly altered. The current-voltage relationship of the mutant
-cells was shifted by
10 mV toward more positive potentials at the lower voltage range. Furthermore, mutant islets secreted less insulin than control islets in the presence of 3 mM glucose. However, insulin secretion from mutant islets was similar to that from control islets when subjected to 6 mM or higher concentrations of glucose. This indicates that overexpression of CaV1.2 subunits indeed compensates for the loss of CaV currents conducted by CaV1.3 subunits and thereby maintains insulin secretion capacity. Hence,
-cell CaV1.3 subunits in wild-type mouse
-cells are likely to play an important role in basal insulin secretion and also stimulus-secretion coupling at the lower range of glucose concentrations (69). The compensatory responses in
-cells may differ between CaV1.2 and CaV1.3 subunit-deficient mice. Apparently, the distinct contribution of CaV1.2 and CaV1.3 subtypes to insulin exocytosis remains to be elucidated.
The selective N-type CaV channel blocker
-conotoxin GVIA has been used to identify N-type CaV channels in
-cells (Table 2). The mouse islet
-cell does not appear to possess N-type CaV channels, as application of
-conotoxin GVIA did not affect the mouse
-cell CaV currents (96). Evidence for the presence of N-type CaV channels in the rat islet
-cell was obtained by measuring [Ca2+]i (80). This study revealed that arachidonic acid induced Ca2+ influx into purified rat pancreatic
-cells (80). The L-type CaV channel blocker nifedipine only partially blocked the effect. Interestingly,
-conotoxin GIVA, an N-type CaV channel blocker, decreased arachidonic acid-induced Ca2+ influx by a magnitude similar to that of nifedipine. This indicates that rat
-cell N-type CaV channels mediate Ca2+ influx induced by arachidonic acid (80). Electrophysiological and pharmacological evidence does not support N-type CaV channels being situated in human
-cells (19). Some groups have detected N-type CaV currents in HIT-15T, RINm5F, and INS-1 cells (89, 91, 96). Contradictory to this, other groups reported that whole cell CaV currents in HIT-15T, RINm5F, and INS-1 cells were insensitive to
-conotoxin GVIA (64, 89, 96). The role of N-type CaV channels in insulin exocytosis is controversial. The N-type CaV channel blocker
-conotoxin GVIA indeed gave a measurable inhibition of the second phase of glucose-induced insulin secretion from rat islets but had no effects on the first phase. The effect on the second phase of glucose-induced insulin secretion was attributed to toxic effects of the high concentration of
-conotoxin GVIA used (53).
-Cell P/Q-type CaV currents have been recorded in various types of
-cells, including mouse, rat, and human islet
-cells as well as INS-1 and RINm5F cell lines (Table 2). Recently, the presence of P/Q-type CaV channels has been verified in the mouse islet
-cell. A mixture of the L-type CaV blocker isradipine and R-type CaV blocker SNX-482 reduced CaV currents recorded from the mouse islet
-cell by
80%. A cocktail of isradipine, SNX-482, and
-agatoxin IVA almost fully blocked mouse
-cell CaV currents (94). The role of P/Q-type CaV channels in stimulus-secretion coupling of mouse
-cells remains to be examined. The involvement of P/Q-type CaV channels in insulin secretion from rat
-cells has been demonstrated by electrophysiological and pharmacological means (58). The P/Q-type CaV channel blocker
-agatoxin IVA partially blocks HVA Ca2+ currents in the rat
-cell and inhibits the DHP-resistant component of glucose-induced insulin secretion by
30% (58). Previous work showed that a portion of CaV currents and Ca2+-dependent insulin secretion in human islet cells remained in the presence of both the L-type CaV channel blocker nifedipine and the N-type CaV channel blocker
-conotoxin GVIA (19). Recently,
25% of human
-cell CaV currents have been verified as P/Q-type CaV currents by application of
-agatoxin IVA. The effect of
-agatoxin IVA on insulin release from human
-cell is significant, but less than that of the L-type CaV channel blocker (96).
It was difficult to evaluate whether the R-type CaV channel was present in
-cells and involved in Ca2+-dependent insulin secretion. These problems were solved by the application of mice lacking the CaV2.3 (
1E) subunit and selective peptide antagonist of the R-type CaV channel (71, 76). Pharmacological manipulation has dissected R-type CaV currents from whole cell CaV currents in mouse islet
-cells and INS-1 cells (Table 2). The CaV2.3 subunit-selective peptide antagonist SNX-482 inhibits
60% of isradipine-resistant CaV currents in mouse islet
-cells (94). Evidence indicates that Ca2+ influx through R-type CaV channels is coupled to insulin exocytosis (28, 76, 105, 106). CaV2.3-deficient mice exhibited disturbances in glucose tolerance and insulin secretion as well as hyperglycemia (76). An appreciable proportion of the increase in mouse
-cell capacitance, reflecting insulin exocytosis in response to depolarizations, can be blocked by SNX-482. Glucose- and KCl-induced insulin secretion from INS-1 cells was inhibited by SNX-482 in a dose-dependent manner (105).
Although the mouse
-cell does not carry T-type CaV channels, they have been identified in human and rat islet
-cells as well as in RINm5F and INS-1 cells (Table 2). Interestingly, the occurrence of T-type CaV channels has been observed in nonobese diabetic (NOD) mouse
-cells (108). The
-cell T-type CaV channel is likely to be a player in stimulus-secretion coupling (13, 52, 68). The T-type CaV channel blocker NiCl2 has been shown to inhibit insulin secretion from INS-1 cells in a dose-dependent manner (13). However, it is not known about the role of the T-type CaV channel in insulin secretion from rat and human islet
-cells. It would be attractive to evaluate the possible contribution of the T-type CaV channel to stimulus-secretion coupling in these islet
-cells.
 |
-CELL CAV CHANNELS AND -CELL DEATH
|
---|
The
-cell CaV channel also plays an important role in the maintenance of
-cell viability. It coordinates with non-voltage-gated Ca2+ channels, Ca2+ buffering systems, and Ca2+ pumps to effectively control dynamics and homeostasis of [Ca2+]i, a life-and-death signal (10, 11, 48, 74). The sophisticated interplay between CaV channels and non-voltage-gated Ca2+ channels and Ca2+ buffering systems as well as Ca2+ pumps in the cell can form an infinity of functional combinations spatially and/or temporally. Some of them play an important role in cell growth, proliferation, and differentiation. Others trigger necrosis and apoptosis. Therefore, it is easy to understand why [Ca2+]i can be either a life or a death signal (11). Generally speaking, Ca2+ influx through the properly opened CaV channels provides cells with a life signal. On the contrary, hyperactivation of CaV channels may result in too high a [Ca2+]i, this divalent cation then serving as a death signal (74). For example, the enhancement of
-cell L-type CaV activity by type 1 diabetic serum causes typical apoptosis (48). Moreover, the long-term L-type CaV channel opening induced by glucose and tolbutamide results in pancreatic
-cell apoptosis (24). Cytokines trigger pancreatic
-cell death through activation of T-type CaV channels (109). The loss of
-cells occurs in both type 1 and type 2 diabetes. Type 1 diabetes is characterized by the absolute loss of pancreatic
-cells; type 2 diabetes is defined by not only the progressive loss of
-cell function but also increased
-cell apoptosis (62). It is likely that hyperactivation of
-cell CaV channels is involved in the loss of
-cells in both type 1 and 2 diabetes (49).
 |
CUSTOMARY MECHANISMS OF -CELL CAV CHANNEL REGULATION
|
---|
Unlike receptors, there are no endogenous selective activators or inhibitors to control individual types of CaV channels. Physiologically, only the degree of membrane depolarization determines the opening of LVA or HVA Ca2+ channels. There must be some other distinct mechanisms to fine tune individual CaV channel functions. The striking structural differences among Ca2+-conducting pore subunits lay a foundation for distinct regulations of CaV channels (15).
Phosphorylation, the most prevalent reversible, covalent modification, is a highly effective means of regulating the activities of target proteins. Regulation of L-type CaV channels by protein phosphorylation is an important example. A variety of protein kinases and phosphatases are present in the pancreatic
-cell (Fig. 2) (22, 70, 97). Activation of cAMP-dependent protein kinase (PKA) markedly increases Ca2+-dependent insulin secretion from permeabilized rat pancreactic islets (102). However, activation of PKA leads to only a marginal increase in L-type CaV currents in mouse pancreatic
-cells, which accounts for a minor proportion of the total increase in insulin exocytosis by PKA (1, 2). A positive impact on insulin exocytosis by protein kinase C (PKC) activation has been found in rat pancreatic
-cells (102). Interestingly, regulation of L-type CaV channels by PKC-mediated phosphorylation is quite different. Acute application of a PKC activator does not affect
-cell CaV channel activity (4). However,
-cell Ca2+ influx through
-cell CaV channels dramatically decreases after deprivation of PKC (4). This means that PKC plays a tonic role in maintaining a proper function of
-cell CaV channels and stimulus-secretion coupling (4). cGMP-dependent protein kinase (PKG) is present in the pancreatic
-cell (118). The effects of PKG activators 8-bromo-cGMP and dibutyryl-cGMP on
-cell CaV channels have been evaluated by measuring [Ca2+]i or patch clamp techniques; however, the results are not consistent. Although [Ca2+]i measurements in combination with application of L-type CaV channel blockers indicate that cGMP increased Ca2+ influx through L-type CaV channels in rat pancreatic
-cells, direct recordings of CaV channel currents show that cGMP does not alter CaV channel activity in mouse
-cells (43, 118). It should be noted that cGMP analogs can produce a direct effect on CaV channels bypassing PKG (20). Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) is expressed in pancreatic
-cells and is involved in the regulation of insulin secretion (22). It is well known that binding of Ca2+/calmodulin to the L-type CaV channel is responsible for Ca2+-dependent inactivation of this channel (98). However, it is unknown whether CaM kinase II per se modulates
-cell Cav channel activity. Tyrosine kinase signaling plays an important role in regulation of
-cell proliferation, survival, and differentiation (112). It is still unclear whether tyrosine kinases affect
-cell CaV channels by phosphorylating them, although Ca2+ influx through
-cell CaV channels has been shown to partially contribute to the increase in [Ca2+]i produced by stimulation of insulin receptors (84). The marginal or no changes in CaV channel activity following activation of the aforementioned protein kinases in primary
-cells indicate that there is a striking difference in CaV channel regulation by protein phosphorylation between primary
-cells and other excitable cells, such as neurons and muscles. It is likely that CaV channels in primary
-cells are highly phosphorylated under basal conditions. Therefore, it is difficult to further phosphorylate these channels following stimulation (1, 2, 4).

View larger version (54K):
[in this window]
[in a new window]
|
Fig. 2. Schematic representation of customary mechanisms of CaV channel regulation by protein phosphorylation, G protein, and Ca2+/calmodulin as well as stimulus-secretion coupling in the pancreatic -cell. AC, adenylyl cyclase; Ca2+/CaM, Ca2+/calmudulin; CAC, citric acid cycle; DAG, diacylglycerol; G, GTP-binding protein; InsP3, inositol 1,4,5-triphosphate; P, phosphoryl group; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC: phospholipase C; PPase, protein phosphatase.
|
|
Several types of protein phosphatases are present in
-cells (2, 29). Inhibition of protein phosphatases has no significant effect on CaV channel activity in mouse pancreatic
-cells but dramatically increases CaV currents in the rat insulin-producing cell line RINm5F, which results in enhancement of insulin secretion from this cell line (2, 29). This indicates that, in some
-cell lines, CaV channels can be surrounded by tonically activated protein phosphatases dominating over protein kinases and thus being sensitive to inhibition of protein phosphatases.
Ca2+ not only flows through CaV channels to produce currents but also functions as the feedback regulator of these channels. The Ca2+-dependent inactivation of L-type CaV channels is thought to offer an important physiological feedback mechanism protecting against Ca2+ overload resulting from activation of these channels during action potentials (98). The Ca2+-dependent inactivation of
-cell L-type CaV channels was first described in the mouse pancreatic
-cell, where the majority of voltage-activated Ca2+ currents are mediated by L-type CaV channels (79). Later on, this phenomenon was also found in
-cells from other species (52). Ca2+-dependent inactivation of
-cell L-type CaV channels results in a Ca2+ current decay during depolarization. The most marked decay of
-cell CaV currents occurs at the potential evoking the largest current. The
-cell CaV current decay disappears when the charge carrier Ca2+ is replaced with Ba2+. Originally, the binding of Ca2+ or some mediators activated by Ca2+ to the CaV channel was proposed to be responsible for the Ca2+-dependent inactivation (52, 79). Now the COOH-terminal IQ domain of the CaV1.2 subunit has been demonstrated to bind Ca2+-activated calmodulin. This binding initiates CaV conformational changes, which cause Ca2+-dependent inactivation (98).
Inhibitory coupling between G proteins and CaV channels is one of the classical pathways of CaV channel regulation. This regulation is voltage dependent and membrane delimited. N-type and P/Q-type CaV channels in particular are modulated by direct interaction with G proteins. CaV channel regulation by the direct membrane-delimited interaction with G protein is characterized by a positive shift in the voltage dependence and a slowing of channel activation (21). The G
-subunit was thought to be responsible for this action on the channel (21, 35). However, later the G
-subunits were demonstrated to play the key role in regulation of CaV channels (21). It is clear that G
-subunits bind to the I-II linker of N-type and P/Q-type CaV channels. The binding site in the I-II linker has been mapped. The QQIER sequence is essential for G
binding (21). Additionally, NH2 and COOH termini of the CaV
1-subunit are also involved in G
-binding (21). It has been suggested that activation of G protein-coupled receptors significantly inhibits insulin secretion via inhibition of
-cell CaV channel activity (27, 39, 40, 50). Indeed, P/Q-type CaV channels are present in pancreatic
-cells (19, 36, 58, 63, 99). However, the L-type CaV channel in insulin-secreting cell lines is the major mediator of the inhibition of insulin secretion by the activation of G protein-coupled receptors, including
2-adrenergic, galanin, and somatostatin receptors (27, 39, 40, 50). Conversely, the stimulation of these G protein-coupled receptors in mouse islet
-cells does not influence voltage-activated Ca2+ influx (82). Moreover, the low conductance G protein-dependent K+ channel is drastically activated by the stimulation of the mouse
-cell
2-adrenergic receptors (85). Indeed, emerging evidence indicates that CaV1.2 channels are negatively regulated by a direct membrane-delimited interaction with G proteins. A recent study shows that the G
-subunits directly bind to cytosolic NH2 and COOH termini of the CaV1.2 subunit and significantly inhibit L-type CaV channel activity. It should be noted that in vitro binding assays and coexpression in Xenopus oocytes were employed in this study (44). Interestingly, it has been demonstrated that the activation of µ-opioid receptors dramatically increases CaV1.3 channel activity (93). Collectively, the molecular mechanisms whereby the activation of G protein-coupled receptors regulate L-type CaV channel activity and insulin secretion remain to be established.
 |
REGULATION OF -CELL L-TYPE CAV CHANNELS BY EXOCYTOTIC PROTEINS
|
---|
In the early 1990s, antibodies against syntaxin or synaptotagmin were reported to coimmunoprecipitate
-conotoxin-binding proteins (8, 57). This was indicative of possible regulation of CaV channels by exocytotic proteins. Considerable efforts have been made to investigate the physical association and functional interaction of CaV channels with exocytotic proteins. The molecular mechanisms of the regulation of N- and P/Q-type CaV channels by exocytotic proteins have been manifested by combining the techniques of electrophysiology, protein chemistry, and molecular biology (12, 15). Although these mechanisms are not involved in the regulation of neuronal L-type CaV channels, they do exert direct control of
-cell L-type CaV channels and represent an additional mechanism whereby the
-cell CaV channel can be regulated. Experimental evidence has demonstrated that the L-type CaV channel has a similar association with the exocytotic machinery as the neuronal N- and P/Q-type CaV channel (47, 51, 113, 116).
Deconvolution analysis of fluorescence images revealed that the expressed CaV1.3 subunit-enhanced green fluorescent protein (EGFP) and enhanced blue fluorescent protein-syntaxin 1 colocalized in the
-cell plasma membrane (116). Furthermore, subcellular fractionation showed that the endogenous CaV1.3 subunit and syntaxin 1A also colocalized in the
-cell plasma membrane. This led to the hypothesis that syntaxin 1A might interact with the CaV1.3 subunit in the pancreatic
-cell, and this was subsequently found to be the case (116). Interestingly, the polyclonal antibody against the intracellular domain of syntaxin 1A efficiently coimmunoprecipitated the CaV1.3 subunit from the
-cell plasma membrane fractions. These results strongly suggest that syntaxin 1A forms a complex with the CaV1.3 subunit of the L-type CaV channel. The physical association of the CaV1.3 subunit with syntaxin 1A exhibits clear functional consequences. On the one hand,
-cell L-type CaV channel activity drastically runs down following anti-syntaxin 1A antibody interference with the formation of a syntaxin 1A-CaV1.3 subunit complex. On the other hand, the dissociation of syntaxin 1A from the CaV1.3 subunit dramatically perturbs insulin exocytosis independently of the rundown of L-type CaV channel activity. This indicates that the syntaxin 1A-CaV1.3 subunit complex plays an important role in maintaining both L-type CaV channel activity and syntaxin 1A function (116).
The
-cell CaV1.2 channel is also modulated by exocytotic proteins (113). Pull-down experiments with His6-fused CaV1.2 subunit peptides show that syntaxin 1A, synaptosome-associated protein of 25 kDa (SNAP-25), and synaptotagmin physically associate with the CaV1.2 channel at the II-III loop of the CaV1.2 subunit (LC753893) (113). The coexpressed syntaxin 1A slightly alters the inactivation and activation rate and significantly decreases the amplitude of CaV1.2 currents recorded in Xenopus oocytes injected with CaV1.2/
2A/
2
. The inhibitory effects are partially reversed by the coexpression of synaptotagmin. The interruption of the physical association of the CaV1.2 channel with exocytotic proteins by the intracellular application of CaV1.2753893 peptide almost completely blocks depolarization-evoked exocytosis without significant influence on Ca2+ influx (113). Similar effects were observed in insulin-secreting cell lines overexpressing syntaxin 1A and 3. Overexpression of syntaxin 1A and 3 dramatically inhibits L-type CaV channel activity and Ca2+-dependent insulin secretion in insulin-secreting cell lines (51).
Modulation of L-type CaV channel activity by distinct domains within SNAP-25 has been characterized in
-cells (47). L-type CaV currents in mouse
-cells are significantly decreased by intracellular application of SNAP-25(1206). The coapplication of CaV1.2753893 peptide occludes the reduction in L-type CaV currents. HIT cells overexpressing or injected with wild-type SNAP-25 show smaller L-type CaV currents than control cells. This inhibition is also prevented by the CaV1.2753893 peptide. Interestingly, expression of SNAP-25(1197) increases L-type CaV currents, and these effects are blocked by the CaV1.2753893 peptide. In contrast, intracellular application of SNAP-25(198206) into untransfected cells significantly reduces L-type CaV currents, these inhibitory effects dominating over the stimulatory effects of SNAP-25(1197) overexpression. The results clearly reveal that the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein SNAP-25 possesses distinct inhibitory and stimulatory domains that act on the L-type CaV channel (47).
Collectively, the
-cell L-type CaV channel physically associates with the exocytotic machinery. This physical association may not only serve as a fine-tuning mechanism of
-cell L-type CaV channel function but also as an anchoring machinery to optimally organize this channel at the site of insulin exocytosis (Fig. 3).
 |
REGULATION OF -CELL L-TYPE CAV CHANNELS BY INOSITOL HEXAKISPHOSPHATE
|
---|
The possibility that inositol hexakisphosphate (InsP6) acts as a general intracellular signaling molecule in native excitable cells is suggested from a number of findings (23, 55, 87, 88). InsP6 levels transiently change in several cell types in response to stimulation (55, 88, 117). Microinjection of InsP6 into neurons of Aplysia induces an initial inward current carried mainly by Na+ and Ca2+ followed by an outward K+ current (92). InsP6 has been shown to enhance insulin exocytosis from permeabilized HIT-T15 cells and mouse islet
-cells through activation of PKC-
(23, 37). Interestingly, InsP6 also potentiates dynamin I-mediated
-cell endocytosis by means of calcineurin-induced dephosphorylation (38).
The aforementioned results attracted us to examine the possible role of InsP6 in the regulation of
-cell CaV channels. As we have learned more recently, InsP6 significantly inhibits the activity of purified catalytic subunits of serine/threonine protein phosphatase types 1, 2A, and 3 as well as corresponding holoenzymes in insulin-secreting cell extracts (55). In addition to the plasma membrane receptor-mediated pathway, glucose stimulation also results in a rapid InsP6 rise in insulin-secreting cells (55). Furthermore, intracellular application of InsP6 dramatically potentiates L-type CaV channel activity in insulin-secreting cell lines (55). These results lead to the conclusion that, under physiological conditions,
-cell L-type CaV channels are activated not only by glucose metabolism-mediated depolarization but also by glucose-induced elevation of intracellular InsP6, which inhibits protein phosphatases and as well activates other mechanisms (see below) leading to an increase in
-cell L-type CaV channel activity (Fig. 3) (55).
The above-mentioned study raises two questions. 1) Does InsP6 selectively modulate L-type CaV channels? 2) Are there other mechanisms involved in the modulation of L-type CaV channels by InsP6? To tackle these questions, we chose hippocampal neurons because they are equipped with all known physiological types of CaV channels, including L-, P/Q-, N-, R-, and T-types, and should also contain other possible InsP6-mediated signaling pathways (14, 33, 34, 101). We observed that intracellular application of InsP6 selectively enhances L-type CaV currents, although multiple types of CaV channels exist in the hippocampal neuron. Interestingly, we found that InsP6 significantly increases adenylyl cyclase (AC) activity in hippocampal membrane preparations without influencing cAMP phosphodiesterase (PDE). Physiological consequences of the InsP6 effect on AC were examined in both biochemical and electrophysiological experiments. In the presence of InsP6, more cAMP is produced by AC in the hippocampal membrane preparation, resulting in a more effective activation of PKA in the hippocampal cytosol, compared with in the absence of InsP6. Furthermore, the effect of 8-(4-chlorophenylthio)-cAMP, a membrane-permeable cAMP analog, on L-type CaV channel activity is counteracted by pretreatment with InsP6 (117).
The combination of our findings in
-cells and in hippocampal neurons leads to the novel view that InsP6 acts as a general intracellular signaling molecule to fine tune L-type CaV channel activity via both inhibition of protein phosphatases and stimulation of the AC-PKA cascade in native excitable cells (Fig. 3).
 |
REGULATION OF -CELL L-TYPE CAV CHANNELS BY TYPE 1 DIABETIC SERUM
|
---|
Under certain pathophysiological conditions, an increased Ca2+ influx through the hyperactivated CaV channels can overload cells with Ca2+. The Ca2+ overload results in both the disintegration of cells (necrosis), through the activity of Ca2+-sensitive proteases, and the activation of the apoptotic cell death program (10, 11, 74). It is clear that a lethal Ca2+ influx occurs in pancreatic
-cells when L-type CaV channels are hyperactivated by exposure to type 1 diabetic serum (Fig. 3) (48). Our initial study revealed that
-cells exposed to type 1 diabetic serum show an increase in L-type Ca2+ currents at both the whole cell and single channel levels. Indeed, an abnormal Ca2+ entry via L-type CaV channels causes a Ca2+ overload in
-cells exposed to type 1 diabetic serum, as manifested by measurements of [Ca2+]i. The Ca2+ overload, in turn, leads to
-cell apoptosis. The apoptotic effect of type 1 diabetic serum is blocked by L-type CaV channel blockers (48).
Although we are still far from understanding the mechanisms whereby type 1 diabetic serum enhances
-cell CaV channel activity and causes
-cell apoptosis, evidence indicates that multiple factors are involved. Fas-specific antibodies in type 1 diabetic serum elevate [Ca2+]i in neuroblastoma cells and cause their apoptosis (78). The rat dorsal root ganglion neurons incubated with the serum from the Bio Bred/Worchester diabetic rat (type 1 diabetic model) display enhancement of both HVA and LVA Ca2+ channel activity, associated with impaired regulation of the inhibitory G protein-CaV channel complex (31, 83). Recently, our group (16) found that incubation with type 1 diabetic serum promotes T-type CaV channel expression in a particular type of neurons with triangular soma in cerebellar granule cell cultures. More recently, we (49) demonstrated that type 1 diabetic serum contains significantly elevated concentrations of apolipoprotein C-III. This serum factor increases L-type CaV channel activity, thereby overloading
-cells with Ca2+, resulting in Ca2+-dependent
-cell apoptosis. Anti-apolipoprotein C-III antibody effectively abolishes both type 1 diabetic serum- and apolipoprotein C-III-induced increases in [Ca2+]i and apoptosis. It is thus possible to postulate that the elevated concentration of apolipoprotein C-III in the blood of type 1 diabetic patients likely aggravates the disease development on top of the autoimmune attack. The mechanisms of
-cell destruction in type 1 diabetes are not fully understood, although T-lymphocyte-mediated
-cell death has been considered as a major one (65). Apparently, the effect of type 1 diabetic serum on
-cells involves both multiple factors in the serum and numerous targets on the
-cells. At the moment, we are searching for additional factors in type 1 diabetic serum, which hyperactivate
-cell CaV channels, and additional targets on
-cells, which mediate
-cell apoptosis.
 |
CONCLUSIONS
|
---|
Heterogeneous CaV channels have been identified in the insulin-secreting
-cell (Table 2). The L-type CaV channel plays a predominant role over other types of CaV channels in [Ca2+]i-triggered insulin exocytosis (5, 89, 96). Besides membrane potential, a variety of signaling pathways, such as protein phosphorylation, Ca2+-dependent inactivation, and G protein interaction modulate
-cell CaV channel activity (1, 2, 4, 27, 29, 39, 40, 50, 52, 55, 79, 93). It must be kept in mind, however, that there are some characteristic features of
-cell CaV channel regulation. For example, activation of PKA induces a marked increase in CaV channel activity in hippocampal neurons, but just a marginal change in that of primary
-cells (1, 2, 117). This suggests that the phosphorylation state of CaV channels in primary
-cells may reach extremely high levels under basal conditions. It will be of interest to explore molecular bases for the characteristic features of
-cell CaV channel regulation. In addition to the aforementioned customary mechanisms, we have also characterized some novel mechanisms of
-cell CaV channel regulation. We have revealed that exocytotic proteins and InsP6 are important players in
-cell CaV channel modulation under physiological conditions and that type 1 diabetic serum hyperactivates
-cell CaV channels and in turn initiates
-cell apoptosis under pathophysiological conditions (16, 47, 48, 55, 116, 117). These findings are summarized in Fig. 3.
Our future goals include defining distinct roles of different types of
-cell CaV channels, identifying
-cell L-type CaV channel-exocytotic protein interaction sites, and exploiting other molecular mechanisms involved in InsP6 regulation of
-cell CaV channels. Our future goals also comprise determining possible roles of human
-cell CaV channel gene mutations in the development of diabetes and probing the exact factors in type 1 diabetic serum responsible for hyperactivation of
-cell CaV channels as well as defining underlying molecular mechanisms.
 |
GRANTS
|
---|
Our work discussed in this review was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-58508), the Swedish Research Council, the Juvenile Diabetes Research Foundation International, the Swedish Diabetes Foundation, the Novo Nordisk Foundation, the Family Stefan Persson Foundation, Beth von Kantzows' Foundation, the Swedish Society of Medicine, the Swedish Foundation for Strategic Research, the Swedish Alzheimer Foundation, and
ke Wiberg's Foundation and funds from Karolinska Institutet.
 |
FOOTNOTES
|
---|
Address for reprint requests and other correspondence: P.-O. Berggren, The Rolf Luft Center for Diabetes Research L3, Dept. of Molecular Medicine, Karolinska Institutet, Karolinska Univ. Hospital Solna, S-171 76 Stockholm, Sweden (E-mail: per-olof.berggren{at}molmed.ki.se)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
 |
REFERENCES
|
---|
- Ammala C, Ashcroft FM, and Rorsman P. Calcium-independent potentiation of insulin release by cyclic AMP in single beta-cells. Nature 363: 356358, 1993.[CrossRef][ISI][Medline]
- Ammala C, Eliasson L, Bokvist K, Berggren PO, Honkanen RE, Sjoholm A, and Rorsman P. Activation of protein kinases and inhibition of protein phosphatases play a central role in the regulation of exocytosis in mouse pancreatic beta cells. Proc Natl Acad Sci USA 91: 43434347, 1994.[Abstract]
- Arikkath J and Campbell KP. Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr Opin Neurobiol 13: 298307, 2003.[CrossRef][ISI][Medline]
- Arkhammar P, Juntti-Berggren L, Larsson O, Welsh M, Nanberg E, Sjoholm A, Kohler M, and Berggren PO. Protein kinase C modulates the insulin secretory process by maintaining a proper function of the beta-cell voltage-activated Ca2+ channels. J Biol Chem 269: 27432749, 1994.[Abstract/Free Full Text]
- Ashcroft FM and Rorsman P. Electrophysiology of the pancreatic beta-cell. Prog Biophys Mol Biol 54: 87143, 1989.[CrossRef][Medline]
- Baldelli P, Hernandez-Guijo JM, Carabelli V, Novara M, Cesetti T, Andres-Mateos E, Montiel C, and Carbone E. Direct and remote modulation of L-channels in chromaffin cells: distinct actions on alpha1C and alpha1D subunits? Mol Neurobiol 29: 7396, 2004.[CrossRef][ISI][Medline]
- Barg S, Ma X, Eliasson L, Galvanovskis J, Gopel SO, Obermuller S, Platzer J, Renstrom E, Trus M, Atlas D, Striessnig J, and Rorsman P. Fast exocytosis with few Ca2+ channels in insulin-secreting mouse pancreatic B cells. Biophys J 81: 33083323, 2001.[Abstract/Free Full Text]
- Bennett MK, Calakos N, and Scheller RH. Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 257: 255259, 1992.[ISI][Medline]
- Berggren PO and Larsson O. Ca2+ and pancreatic B-cell function. Biochem Soc Trans 22: 1218, 1994.[ISI][Medline]
- Berridge MJ, Bootman MD, and Lipp P. Calciuma life and death signal. Nature 395: 645648, 1998.[CrossRef][ISI][Medline]
- Berridge MJ, Lipp P, and Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1: 1121, 2000.[CrossRef][ISI][Medline]
- Bezprozvanny I, Scheller RH, and Tsien RW. Functional impact of syntaxin on gating of N-type and Q-type calcium channels. Nature 378: 623626, 1995.[CrossRef][ISI][Medline]
- Bhattacharjee A, Whitehurst RMJ, Zhang M, Wang L, and Li M. T-type calcium channels facilitate insulin secretion by enhancing general excitability in the insulin-secreting beta-cell line, INS-1. Endocrinology 138: 37353740, 1997.[Abstract/Free Full Text]
- Catterall WA. Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. Cell Calcium 24: 307323, 1998.[ISI][Medline]
- Catterall WA. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16: 521555, 2000.[CrossRef][ISI][Medline]
- Chandra J, Yang SN, Kohler M, Zaitsev S, Juntti-Berggren L, Berggren PO, Zhivotovsky B, and Orrenius S. Effects of serum from patients with type 1 diabetes on primary cerebellar granule cells. Diabetes 50: S77S81, 2001.[Free Full Text]
- Chen YH, Li MH, Zhang Y, He LL, Yamada Y, Fitzmaurice A, Shen Y, Zhang H, Tong L, and Yang J. Structural basis of the alpha1-beta subunit interaction of voltage-gated Ca2+ channels. Nature 429: 675680, 2004.[CrossRef][ISI][Medline]
- Curtis BM and Catterall WA. Purification of the calcium antagonist receptor of the voltage-sensitive calcium channel from skeletal muscle transverse tubules. Biochemistry 23: 21132118, 1984.[ISI][Medline]
- Davalli AM, Biancardi E, Pollo A, Socci C, Pontiroli AE, Pozza G, Clementi F, Sher E, and Carbone E. Dihydropyridine-sensitive and -insensitive voltage-operated calcium channels participate in the control of glucose-induced insulin release from human pancreatic beta cells. J Endocrinol 150: 195203, 1996.[Abstract]
- Doerner D and Alger BE. Cyclic GMP depresses hippocampal Ca2+ current through a mechanism independent of cGMP-dependent protein kinase. Neuron 1: 693699, 1988.[ISI][Medline]
- Dolphin AC. G protein modulation of voltage-gated calcium channels. Pharmacol Rev 55: 607627, 2003.[Abstract/Free Full Text]
- Easom RA. CaM kinase II: a protein kinase with extraordinary talents germane to insulin exocytosis. Diabetes 48: 675684, 1999.[Abstract]
- Efanov AM, Zaitsev SV, and Berggren PO. Inositol hexakisphosphate stimulates non-Ca2+-mediated and primes Ca2+-mediated exocytosis of insulin by activation of protein kinase C. Proc Natl Acad Sci USA 94: 44354439, 1997.[Abstract/Free Full Text]
- Efanova IB, Zaitsev SV, Zhivotovsky B, Kohler M, Efendic S, Orrenius S, and Berggren PO. Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A process dependent on intracellular Ca2+ concentration. J Biol Chem 273: 3350133507, 1998.[Abstract/Free Full Text]
- Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E, Schwartz A, Snutch TP, Tanabe T, Birnbaumer L, Tsien RW, and Catterall WA. Nomenclature of voltage-gated calcium channels. Neuron 25: 533535, 2000.[ISI][Medline]
- Gao B, Sekido Y, Maximov A, Saad M, Forgacs E, Latif F, Wei MH, Lerman M, Lee JH, Perez-Reyes E, Bezprozvanny I, and Minna JD. Functional properties of a new voltage-dependent calcium channel alpha2delta auxiliary subunit gene (CACNA2D2). J Biol Chem 275: 1223712242, 2000.[Abstract/Free Full Text]
- Gillison SL, Straub SG, and Sharp GW. The alpha2-adrenergic receptor is more effective than the galanin receptor in activating G-proteins in RINm5F beta-cell membranes. Diabetes 46: 401407, 1997.[Abstract]
- Grabsch H, Pereverzev A, Weiergraber M, Schramm M, Henry M, Vajna R, Beattie RE, Volsen SG, Klockner U, Hescheler J, and Schneider T. Immunohistochemical detection of alpha1E voltage-gated Ca2+ channel isoforms in cerebellum, INS-1 cells, and neuroendocrine cells of the digestive system. J Histochem Cytochem 47: 981994, 1999.[Abstract/Free Full Text]
- Haby C, Larsson O, Islam MS, Aunis D, Berggren PO, and Zwiller J. Inhibition of serine/threonine protein phosphatases promotes opening of voltage-activated L-type Ca2+ channels in insulin-secreting cells. Biochem J 298: 341346, 1994.[ISI][Medline]
- Hagiwara S, Ozawa S, and Sand O. Voltage clamp analysis of two inward current mechanisms in the egg cell membrane of a starfish. J Gen Physiol 65: 617644, 1975.[Abstract]
- Hall KE, Sima AA, and Wiley JW. Voltage-dependent calcium currents are enhanced in dorsal root ganglion neurones from the Bio Bred/Worchester diabetic rat. J Physiol 486: 313322, 1995.[Abstract]
- Hamill OP, Marty A, Neher E, Sakmann B, and Sigworth FJ. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 391: 85100, 1981.[ISI][Medline]
- Hell JW, Westenbroek RE, Warner C, Ahlijanian MK, Prystay W, Gilbert MM, Snutch TP, and Catterall WA. Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel alpha 1 subunits. J Cell Biol 123: 949962, 1993.[Abstract]
- Hell JW, Yokoyama CT, Breeze LJ, Chavkin C, and Catterall WA. Phosphorylation of presynaptic and postsynaptic calcium channels by cAMP-dependent protein kinase in hippocampal neurons. EMBO J 14: 30363044, 1995.[Abstract]
- Hille B. Modulation of ion-channel function by G-protein-coupled receptors. Trends Neurosci 17: 531536, 1994.[CrossRef][ISI][Medline]
- Horvath A, Szabadkai G, Varnai P, Aranyi T, Wollheim CB, Spat A, and Enyedi P. Voltage dependent calcium channels in adrenal glomerulosa cells and in insulin producing cells. Cell Calcium 23: 3342, 1998.[ISI][Medline]
- Hoy M, Berggren PO, and Gromada J. Involvement of protein kinase C-epsilon in inositol hexakisphosphate-induced exocytosis in mouse pancreatic beta-cells. J Biol Chem 278: 3516835171, 2003.[Abstract/Free Full Text]
- Hoy M, Efanov AM, Bertorello AM, Zaitsev SV, Olsen HL, Bokvist K, Leibiger B, Leibiger IB, Zwiller J, Berggren PO, and Gromada J. Inositol hexakisphosphate promotes dynamin I-mediated endocytosis. Proc Natl Acad Sci USA 99: 67736777, 2002.[Abstract/Free Full Text]
- Hsu WH, Xiang HD, Rajan AS, and Boyd AE. Activation of alpha 2-adrenergic receptors decreases Ca2+ influx to inhibit insulin secretion in a hamster beta-cell line: an action mediated by a guanosine triphosphate-binding protein. Endocrinology 128: 958964, 1991.[Abstract]
- Hsu WH, Xiang HD, Rajan AS, Kunze DL, and Boyd AE. Somatostatin inhibits insulin secretion by a G-protein-mediated decrease in Ca2+ entry through voltage-dependent Ca2+ channels in the beta cell. J Biol Chem 266: 837843, 1991.[Abstract/Free Full Text]
- Huang L, Bhattacharjee A, Taylor JT, Zhang M, Keyser BM, Marrero L, and Li M. [Ca2+]i regulates trafficking of CaV1.3 (
1D Ca2+ channel) in insulin secreting cells. Am J Physiol Cell Physiol 286: C213C221, 2004.[Abstract/Free Full Text]
- Hullin R, Singer-Lahat D, Freichel M, Biel M, Dascal N, Hofmann F, and Flockerzi V. Calcium channel beta subunit heterogeneity: functional expression of cloned cDNA from heart, aorta and brain. EMBO J 11: 885890, 1992.[Abstract]
- Ishikawa T, Kaneko Y, Sugino F, and Nakayama K. Two distinct effects of cGMP on cytosolic Ca2+ concentration of rat pancreatic beta-cells. J Pharm Sci 91: 4146, 2003.[CrossRef][ISI]
- Ivanina T, Blumenstein Y, Shistik E, Barzilai R, and Dascal N. Modulation of L-type Ca2+ channels by G

and calmodulin via interactions with N and C termini of alpha 1C. J Biol Chem 275: 3984639854, 2000.[Abstract/Free Full Text]
- Iwashima Y, Abiko A, Ushikubi F, Hata A, Kaku K, Sano H, and Eto M. Downregulation of the voltage-dependent calcium channel (VDCC) beta-subunit mRNAs in pancreatic islets of type 2 diabetic rats. Biochem Biophys Res Commun 280: 923932, 2001.[CrossRef][ISI][Medline]
- Iwashima Y, Pugh W, Depaoli AM, Takeda J, Seino S, Bell GI, and Polonsky KS. Expression of calcium channel mRNAs in rat pancreatic islets and downregulation after glucose infusion. Diabetes 42: 948955, 1993.[Abstract]
- Ji J, Yang SN, Huang X, Li X, Sheu L, Diamant N, Berggren PO, and Gaisano HY. Modulation of L-type Ca2+ channels by distinct domains within SNAP-25. Diabetes 51: 14251436, 2002.[Abstract/Free Full Text]
- Juntti-Berggren L, Larsson O, Rorsman P, Ammala C, Bokvist K, Wahlander K, Nicotera P, Dypbukt J, Orrenius S, Hallberg A, and Berggren PO. Increased activity of L-type Ca2+ channels exposed to serum from patients with type I diabetes. Science 261: 8690, 1993.[ISI][Medline]
- Juntti-Berggren L, Refai E, Appelskog I, Andersson M, Imreh G, Dekki N, Uhles S, Yu L, Griffiths WJ, Zaitsev S, Leibiger I, Yang SN, Olivecrona G, Jornvall H, and Berggren PO. Apolipoprotein CIII promotes Ca2+-dependent
cell death in type 1 diabetes. Proc Natl Acad Sci USA 101: 1009010094, 2004.[Abstract/Free Full Text]
- Kalkbrenner F, Degtiar VE, Schenker M, Brendel S, Zobel A, Heschler J, Wittig B, and Schultz G. Subunit composition of Go proteins functionally coupling galanin receptors to voltage-gated calcium channels. EMBO J 14: 47284737, 1995.[Abstract]
- Kang Y, Huang X, Pasyk EA, Ji J, Holz GG, Wheeler MB, Tsushima RG, and Gaisano HY. Syntaxin-3 and syntaxin-1A inhibit L-type calcium channel activity, insulin biosynthesis and exocytosis in beta-cell lines. Diabetologia 45: 231241, 2002.[CrossRef][ISI][Medline]
- Kelly RP, Sutton R, and Ashcroft FM. Voltage-activated calcium and potassium currents in human pancreatic beta-cells. J Physiol 443: 175192, 1991.[Abstract]
- Komatsu M, Yokokawa N, Takeda T, Nagasawa Y, Aizawa T, and Yamada T. Pharmacological characterization of the voltage-dependent calcium channel of pancreatic B-cell. Endocrinology 125: 20082014, 1989.[Abstract]
- Kozak JA and Logothetis DE. A calcium-dependent chloride current in insulin-secreting beta TC-3 cells. Pflügers Arch 433: 679690, 1997.[CrossRef][ISI][Medline]
- Larsson O, Barker CJ, Sjoholm A, Carlqvist H, Michell RH, Bertorello A, Nilsson T, Honkanen RE, Mayr GW, Zwiller J, and Berggren PO. Inhibition of phosphatases and increased Ca2+ channel activity by inositol hexakisphosphate. Science 278: 471474, 1997.[Abstract/Free Full Text]
- Leiser M and Fleischer N. cAMP-dependent phosphorylation of the cardiac-type alpha 1 subunit of the voltage-dependent Ca2+ channel in a murine pancreatic beta-cell line. Diabetes 45: 14121418, 1996.[Abstract]
- Leveque C, Hoshino T, David P, Shoji-Kasai Y, Leys K, Omori A, Lang B, Far OE, Sato K, Martin-Moutot N, Newsom-Davis J, Takahashi M, and Seagar MJ. The synaptic vesicle protein synaptotagmin associates with calcium channels and is a putative Lambert-Eaton myasthenic syndrome antigen. Proc Natl Acad Sci USA 89: 36253629, 1992.[Abstract]
- Ligon B, Boyd AE, and Dunlap K. Class A calcium channel variants in pancreatic islets and their role in insulin secretion. J Biol Chem 273: 1390513911, 1998.[Abstract/Free Full Text]
- Llinas R, Sugimori M, Lin JW, and Cherksey B. Blocking and isolation of a calcium channel from neurons in mammals and cephalopods utilizing a toxin fraction (FTX) from funnel-web spider poison. Proc Natl Acad Sci USA 86: 16891693, 1989.[Abstract]
- Llinas R and Yarom Y. Properties and distribution of ionic conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro. J Physiol 315: 569584, 1981.[Abstract]
- Lux HD and Nagy K. Single channel Ca2+ currents in Helix pomatia neurons. Pflügers Arch 391: 252254, 1981.[CrossRef][ISI][Medline]
- Maedler K, Spinas GA, Lehmann R, Sergeev P, Weber M, Fontana A, Kaiser N, and Donath MY. Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets. Diabetes 50: 16831690, 2001.[Abstract/Free Full Text]
- Magnelli V, Pollo A, Sher E, and Carbone E. Block of non-L-, non-N-type Ca2+ channels in rat insulinoma RINm5F cells by omega-agatoxin IVA and omega-conotoxin MVIIC. Pflügers Arch 429: 762771, 1995.[CrossRef][ISI][Medline]
- Marchetti C, Amico C, Podesta D, and Robello M. Inactivation of voltage-dependent calcium current in an insulinoma cell line. Eur Biophys J 23: 5158, 1994.[ISI][Medline]
- Mathis D, Vence L, and Benoist C. beta-Cell death during progression to diabetes. Nature 414: 792798, 2001.[CrossRef][ISI][Medline]
- Mikami A, Imoto K, Tanabe T, Niidome T, Mori Y, Takeshima H, Narumiya S, and Numa S. Primary structure and functional expression of the cardiac dihydropyridine-sensitive calcium channel. Nature 340: 230233, 1989.[CrossRef][ISI][Medline]
- Minami K, Yokokura M, Ishizuka N, and Seino S. Normalization of intracellular Ca2+ induces a glucose-responsive state in glucose-unresponsive beta-cells. J Biol Chem 277: 2527725282, 2002.[Abstract/Free Full Text]
- Misler S, Barnett DW, Gillis KD, and Pressel DM. Electrophysiology of stimulus-secretion coupling in human beta-cells. Diabetes 41: 12211228, 1992.[Abstract]
- Namkung Y, Skrypnyk N, Jeong MJ, Lee T, Lee MS, Kim HL, Chin H, Suh PG, Kim SS, and Shin HS. Requirement for the L-type Ca2+ channel alpha1D subunit in postnatal pancreatic beta cell generation. J Clin Invest 108: 10151022, 2001.[Abstract/Free Full Text]
- Nesher R, Anteby E, Yedovizky M, Warwar N, Kaiser N, and Cerasi E. Beta-cell protein kinases and the dynamics of the insulin response to glucose. Diabetes 51: S68S73, 2002.[Abstract/Free Full Text]
- Newcomb R, Szoke B, Palma A, Wang G, Chen X, Hopkins W, Cong R, Miller J, Urge L, Tarczy-Hornoch K, Loo JA, Dooley DJ, Nadasdi L, Tsien RW, Lemos J, and Miljanich G. Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas. Biochemistry 37: 1535315362, 1998.[CrossRef][ISI][Medline]
- Ohta M, Nelson J, Nelson D, Meglasson MD, and Erecinska M. Effect of Ca2+ channel blockers on energy level and stimulated insulin secretion in isolated rat islets of Langerhans. J Pharmacol Exp Ther 264: 3540, 1993.[Abstract]
- Opatowsky Y, Chen CC, Campbell KP, and Hrsch JA. Structural analysis of the voltage-dependent calcium channel beta subunit functional core and its complex with the alpha1 interaction domain. Neuron 42: 387399, 2004.[CrossRef][ISI][Medline]
- Orrenius S, Zhivotovsky B, and Nicotera P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4: 552565, 2003.[CrossRef][ISI][Medline]
- Passafaro M, Codignola A, Rogers M, Cooke I, and Sher E. Modulation of N-type calcium channels translocation in RINm5F insulinoma cells. Pharmacol Res 41: 325334, 2000.[CrossRef][ISI][Medline]
- Pereverzev A, Mikhna M, Vajna R, Gissel C, Henry M, Weiergraber M, Hescheler J, Smyth N, and Schneider T. Disturbances in glucose-tolerance, insulin-release, and stress-induced hyperglycemia upon disruption of the Cav2.3 (alpha 1E) subunit of voltage-gated Ca2+ channels. Mol Endocrinol 16: 884895, 2002.[Abstract/Free Full Text]
- Perez-Reyes E, Wei XY, Castellano A, and Birnbaumer L. Molecular diversity of L-type calcium channels. Evidence for alternative splicing of the transcripts of three non-allelic genes. J Biol Chem 265: 2043020436, 1990.[Abstract/Free Full Text]
- Pittenger GL, Liu D, and Vinik AI. The apoptotic death of neuroblastoma cells caused by serum from patients with insulin-dependent diabetes and neuropathy may be Fas-mediated. J Neuroimmunol 76: 153160, 1997.[CrossRef][ISI][Medline]
- Plant TD. Properties and calcium-dependent inactivation of calcium currents in cultured mouse pancreatic B-cells. J Physiol 404: 731747, 1988.[Abstract]
- Ramanadham S and Turk J. omega-Conotoxin inhibits glucose- and arachidonic acid-induced rises in intracellular Ca2+ in rat pancreatic islet beta-cells. Cell Calcium 15: 259264, 1994.[CrossRef][ISI][Medline]
- Randall A and Tsien RW. Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons. J Neurosci 15: 29953012, 1995.[Abstract]
- Renstrom E, Ding WG, Bokvist K, and Rorsman P. Neurotransmitter-induced inhibition of exocytosis in insulin-secreting beta cells by activation of calcineurin. Neuron 17: 513522, 1996.[ISI][Medline]
- Ristic H, Srinivasan S, Hall KE, Sima AA, and Wiley JW. Serum from diabetic BB/W rats enhances calcium currents in primary sensory neurons. J Neurophysiol 80: 12361244, 1998.[Abstract/Free Full Text]
- Roper MG, Qian WJ, Zhang BB, Kulkarni RN, Kahn CR, and Kennedy RT. Effect of the insulin mimetic L-783281 on intracellular Ca2+ and insulin secretion from pancreatic beta-cells. Diabetes 51: S43S49, 2002.[Abstract/Free Full Text]
- Rorsman P, Bokvist K, Ammala C, Arkhammar P, Berggren PO, Larsson O, and Wahlander K. Activation by adrenaline of a low-conductance G protein-dependent K+ channel in mouse pancreatic B cells. Nature 349: 7779, 1991.[CrossRef][ISI][Medline]
- Safayhi H, Haase H, Kramer U, Bihlmayer A, Roenfeldt M, Ammon HP, Froschmayr M, Cassidy TN, Morano I, Ahlijanian MK, and Striessnig J. L-type calcium channels in insulin-secreting cells: biochemical characterization and phosphorylation in RINm5F cells. Mol Endocrinol 11: 619629, 1997.[Abstract/Free Full Text]
- Sasakawa N, Ferguson JE, Sharif M, and Hanley MR. Attenuation of agonist-induced desensitization of the rat substance P receptor by microinjection of inositol pentakis- and hexakisphosphates in Xenopus laevis oocytes. Mol Pharmacol 46: 380385, 1994.[Abstract]
- Sasakawa N, Nakaki T, Kakinuma E, and Kato R. Increase in inositol tris-, pentakis- and hexakisphosphates by high K+ stimulation in cultured rat cerebellar granule cells. Brain Res 623: 155160, 1993.[CrossRef][ISI][Medline]
- Satin LS. Localized calcium influx in pancreatic beta-cells: its significance for Ca2+-dependent insulin secretion from the islets of Langerhans. Endocr J 13: 251262, 2000.[CrossRef]
- Satin LS and Cook DL. Voltage-gated Ca2+ current in pancreatic B-cells. Pflügers Arch 404: 385387, 1985.[CrossRef][ISI][Medline]
- Satin LS, Tavalin SJ, Kinard TA, and Teague J. Contribution of L- and non-L-type calcium channels to voltage-gated calcium current and glucose-dependent insulin secretion in HIT-T15 cells. Endocrinology 136: 45894601, 1995.[Abstract]
- Sawada M, Ichinose M, and Maeno T. Intracellularly injected inositol hexakisphosphate induces a biphasic current in identified neurons of Aplysia. Neurosci Lett 106: 328333, 1989.[CrossRef][ISI][Medline]
- Scholze A, Plant TD, Dolphin AC, and Nurnberg B. Functional expression and characterization of a voltage-gated CaV1.3 (alpha1D) calcium channel subunit from an insulin-secreting cell line. Mol Endocrinol 15: 12111221, 2001.[Abstract/Free Full Text]
- Schulla V, Renstrom E, Feil R, Feil S, Franklin I, Gjinovci A, Jing XJ, Laux D, Lundquist I, Magnuson MA, Obermuller S, Olofsson CS, Salehi A, Wendt A, Klugbauer N, Wollheim CB, Rorsman P, and Hofmann F. Impaired insulin secretion and glucose tolerance in beta cell-selective Cav1.2 Ca2+ channel null mice. EMBO J 22: 38443854, 2003.[Abstract/Free Full Text]
- Seino S, Chen L, Seino M, Blondel O, Takeda J, Johnson JH, and Bell GI. Cloning of the alpha 1 subunit of a voltage-dependent calcium channel expressed in pancreatic beta cells. Proc Natl Acad Sci USA 89: 584588, 1992.[Abstract]
- Sher E, Giovannini F, Codignola A, Passafaro M, Giorgi-Rossi P, Volsen S, Craig P, Davalli A, and Carrera P. Voltage-operated calcium channel heterogeneity in pancreatic beta cells: physiopathological implications. J Bioenerg Biomembr 35: 687696, 2003.[CrossRef][ISI][Medline]
- Sim AT, Baldwin ML, Rostas JA, Holst J, and Ludowyke RI. The role of serine/threonine protein phosphatases in exocytosis. Biochem J 373: 641659, 2003.[CrossRef][ISI][Medline]
- Soldatov NM. Ca2+ channel moving tail: link between Ca2+-induced inactivation and Ca2+ signal transduction. Trends Pharmacol Sci 24: 167171, 2003.[CrossRef][ISI][Medline]
- Takahashi E, Miyamoto N, and Nagasu T. Analysis of the 5'-upstream region of mouse P/Q-type Ca2+ channel alpha1A subunit gene for expression in pancreatic islet beta cells using transgenic mice and HIT-T15 cells. J Mol Endocrinol 24: 225232, 2000.[Abstract/Free Full Text]
- Takiyama Y, Sakoe K, Namekawa M, Soutome M, Esumi E, Ogawa T, Ishikawa K, Mizusawa H, Nakano I, and Nishizawa M. A Japanese family with spinocerebellar ataxia type 6 which includes three individuals homozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene. J Neurol Sci 158: 141147, 1998.[CrossRef][ISI][Medline]
- Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, and Bayliss DA. Differential distribution of three members of a gene family encoding low voltage-activated T-type calcium channels. J Neurosci 19: 18951911, 1999.[Abstract/Free Full Text]
- Tamagawa T, Niki H, and Niki A. Insulin release independent of a rise in cytosolic free Ca2+ by forskolin and phorbol ester. FEBS Lett 183: 430432, 1985.[CrossRef][ISI][Medline]
- Tanabe T, Takeshima H, Mikami A, Flockerzi V, Takahashi H, Kangawa K, Kojima M, Matsuo H, Hirose T, and Numa S. Primary structure of the receptor for calcium channel blockers from skeletal muscle. Nature 328: 313318, 1987.[CrossRef][ISI][Medline]
- Tsien RW, Lipscombe D, Madison DV, Bley KR, and Fox AP. Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci 11: 431438, 1988.[CrossRef][ISI][Medline]
- Vajna R, Klockner U, Pereverzev A, Weiergraber M, Chen X, Miljanich G, Klugbauer N, Hescheler J, Perez-Reyes E, and Schneider T. Functional coupling between "R-type" Ca2+ channels and insulin secretion in the insulinoma cell line INS-1. Eur J Biochem 268: 10661075, 2001.[Abstract/Free Full Text]
- Vajna R, Schramm M, Pereverzev A, Arnhold S, Grabsch H, Klockner U, Perez-Reyes E, Hescheler J, and Schneider T. New isoform of the neuronal Ca2+ channel alpha1E subunit in islets of Langerhans and kidneydistribution of voltage-gated Ca2+ channel alpha1 subunits in cell lines and tissues. Eur J Biochem 257: 274285, 1998.[Abstract]
- Van Petegem F, Clark KA, Chatelain FC, and Minor DL Jr. Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain. Nature 429: 671675, 2004.[CrossRef][ISI][Medline]
- Wang L, Bhattacharjee A, Fu J, and Li M. Abnormally expressed low voltage-activated calcium channels in beta-cells from NOD mice and a related clonal cell line. Diabetes 45: 16781683, 1996.[Abstract]
- Wang L, Bhattacharjee A, Zuo Z, Hu F, Honkanen RE, Berggren PO, and Li M. A low voltage-activated Ca2+ current mediates cytokine-induced pancreatic beta-cell death. Endocrinology 140: 12001204, 1999.[Abstract/Free Full Text]
- Wang MC, Collins RF, Ford RC, Berrow S, Dolphin AC, and Kitmitto A. The three-dimensional structure of the cardiac L-type voltage-gated calcium channel: Comparison with the skeletal muscle form reveals a common architectural motif. J Biol Chem 279: 71597168, 2003.[CrossRef][ISI][Medline]
- Wang MC, Velarde G, Ford RC, Berrow NS, Dolphin AC, and Kitmitto A. 3D structure of the skeletal muscle dihydropyridine receptor. J Mol Biol 323: 8598, 2002.[CrossRef][ISI][Medline]
- Welsh M, Anneren C, Lindholm C, Kriz V, and Oberg-Welsh C. Role of tyrosine kinase signaling for beta-cell replication and survival. Ups J Med Sci 105: 715, 2000.[ISI][Medline]
- Wiser O, Trus M, Hernandez A, Renstrom E, Barg S, Rorsman P, and Atlas D. The voltage sensitive Lc-type Ca2+ channel is functionally coupled to the exocytotic machinery. Proc Natl Acad Sci USA 96: 248253, 1999.[Abstract/Free Full Text]
- Yamada Y, Kuroe A, Li Q, Someya Y, Kubota A, Ihara Y, Tsuura Y, and Seino Y. Genomic variation in pancreatic ion channel genes in Japanese type 2 diabetic patients. Diabetes Metab Res Rev 17: 213216, 2001.[CrossRef][ISI][Medline]
- Yamada Y, Masuda K, Li Q, Ihara Y, Kubota A, Miura T, Nakamura K, Fujii Y, Seino S, and Seino Y. The structures of the human calcium channel alpha 1 subunit (CACNL1A2) and beta subunit (CACNLB3) genes. Genomics 27: 312319, 1995.[CrossRef][ISI][Medline]
- Yang SN, Larsson O, Branstrom R, Bertorello AM, Leibiger Leibiger IB, Moede T, Kohler M, Meister B, and Berggren PO. Syntaxin 1 interacts with the LD subtype of voltage-gated Ca2+ channels in pancreatic beta cells. Proc Natl Acad Sci USA 96: 1016410169, 1999.[Abstract/Free Full Text]
- Yang SN, Yu J, Mayr GW, Hofmann F, Larsson O, and Berggren PO. Inositol hexakisphosphate increases L-type Ca2+ channel activity by stimulation of adenylyl cyclase. FASEB J 15: 17531763, 2001.[Abstract/Free Full Text]
- Zaitsev SV, Appelskog IB, Kapelioukh IL, Yang SN, Kohler M, Efendic S, and Berggren PO. Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis. Diabetes 50: S70S76, 2001.[Free Full Text]
- Zhuang H, Bhattacharjee A, Hu F, Zhang M, Goswami T, Wang L, Wu S, Berggren PO, and Li M. Cloning of a T-type Ca2+ channel isoform in insulin-secreting cells. Diabetes 49: 5964, 2000.[Abstract]