Subunit of Voltage-activated Calcium Channels*
Myoung-Goo Kang
and
Kevin P. Campbell
From the
Howard Hughes Medical Institute, Department of Physiology and Biophysics and Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242
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INTRODUCTION
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Voltage-activated Ca2+ channels play a major role in many fundamental physiological processes including neurotransmission, muscle contraction, intracellular signaling, hormone secretion, and development. Therefore, an understanding of the structure and regulation of Ca2+ channels is critical for the comprehension of these physiological phenomena. Five types of high voltage-activated Ca2+ channels (named L-, N-, P-, Q-, and R-type) and one type of low voltage-activated Ca2+ channel (known as T-type) have been identified based on the pharmacological and biophysical characteristics of native currents. Voltage-activated Ca2+ channels (called Ca2+ channel or Cav hereafter) consist of four subunits:
1,
,
2
, and
. The
1 subunit is the main subunit responsible for ion conduction, voltage sensing, and binding of Ca2+ channel-specific drugs and toxins. Ten
1 subunits have been cloned and classified as
11.1 (
1S),
11.2 (
1C),
11.3 (
1D),
11.4 (
1F),
12.1 (
1A),
12.2 (
1B),
12.3 (
1E),
13.1 (
1G),
13.2 (
1H), and
13.3 (
1I). The
and
2
subunits are auxiliary proteins that modulate the properties of the Ca2+ current (13). Four isoforms of the
subunit (
1,
2,
3, and
4) and four isoforms of the
2
subunit (
2
-1,
2
-2,
2
-3, and
2
-4) have been identified. An additional auxiliary subunit,
, initially detected in skeletal muscle Ca2+ channels, has been recently associated with neuronal Ca2+ channels (46). The study of Ca2+ channel regulation by auxiliary subunits has been focused on
and
2
subunits and demonstrated positive regulation of functional activities of Ca2+ channels by these proteins. The
and
2
subunits can increase current amplitude and cause various changes in current kinetics and voltage dependence by increasing the number of channels at the plasma membrane and/or causing allosteric modulations of the
1 subunits (7).
The skeletal
subunit (
1) was first purified and characterized through biochemical studies with the other subunits of skeletal muscle Ca2+ channels (8, 9) followed by cloning of its cDNA (10, 11). The
subunit has not been as extensively studied as the
and
2
subunits. The muscle-preferential expression of
1 might be a reason that
1 has not been studied in as great detail as the other auxiliary subunits. However, recent genetic studies revealed the existence of a
subunit isoform in the brain whose lack of expression is responsible for the epileptic and ataxic phenotype of the stargazer mouse (4). The discovery of a novel neuronal
(
2) and its relevance to epilepsy and ataxia has drawn much attention to the study of Ca2+ channel
subunits. Subsequently, six additional
subunit isoforms have been identified through DNA data base searches based on sequence homology to
1 and
2 (1216). Furthermore, mutations in Ca2+ channel subunits, including
mutations, have recently been implicated in a number of human and/or animal neurological disorders, drawing even more attention to the study of Ca2+ channel modulation by its auxiliary subunits.
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Characterization and Classification of Subunit Isoforms
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All eight
subunit isoforms (
18) are characterized by four predicted transmembrane domains, intracellular N and C termini, and the first extracellular loop that includes a signature motif (GLWXXC), a conserved N-glycosylation site, and a pair of conserved cysteine residues that may form a disulfide linkage in the first extracellular loop (Fig. 1). Phylogenetic analyses have suggested that all
subunits are derived from a single ancestral gene through gene duplication (15, 16). Based on the phylogenetic analyses, sequence homologies, and tissue distribution, the
subunits have been categorized into two groups: skeletal
(
1 and
6) and neuronal
(
25 and
78) (15, 16). The
1 and
6 subunits are classified as skeletal muscle
subunits based on their predominant expression in skeletal muscle and relatively short C terminus as well as the high sequence homology (62.5% similarity) between them. In addition, a short form of
6 constituted by two instead of four transmembrane domains was reported (15, 16). The
25 and
78 subunits are classified as neuronal
subunits based on their predominant expression in neuronal tissues, relatively long C terminus, and the sequence homology (29.590.7% similarity) among them. The neuronal
subunits can be subdivided into two groups. The
24 and
8 share higher homology than
5 and
7. PDZ binding motifs at the end of C termini of the neuronal
subunits also differentiate the two groups of neuronal
subunits. The
24 and
8 have the same PDZ binding motif (R(R/K)TTPV) at the end of C termini, which differs from the potential PDZ binding motif (S(T/S)SPC) of the
5 and
7 (16). The genes of
5 and
7 subunits share a distinct intron/exon configuration, a five-exon structure rather than the four-exon structure of the other
genes (16, 17). In addition,
8 differs from the other neuronal
subunits because of its unusual translation initiation codon (3 AXXCTGG +4) and as it contains the longest C terminus (16). The N- and C-terminal regions of
8 also have extensive C/G nucleotide-rich regions (15).
There has been confusion about the sequences of
5 and
7. The amino acid sequence of the mouse
5 reported by Klugbauer et al. (14) was quite different from that of human
5 reported by Burgess et al. (13, 15). Chu et al. (16) performed a comprehensive analysis of the difference and suggested a new version of the
5 sequence (16). Based on the new study it seems that the mouse
5 reported by Klugbauer et al. (14) does not actually belong to the
family and that the C-terminal sequence of human
5 by Burgess et al. (13, 15) should be modified (16). The C-terminal sequence of
7 was also modified as
5 by two recent studies (16, 17). Therefore, the new sequences of
5 and
7 genes are different from those of the original reports. The new sequences of
5 and
7 have much longer C termini than those of the originals, resulting in C-terminal length similar to that of the other neuronal
subunits.
In addition, it has been suggested that
may belong to the claudin family, a group of cell adhesion proteins in tight junctions (15, 18). Claudins are similar to neuronal
subunits in that they have four predicted transmembrane domains, a C-terminal PDZ binding domain, and the first extracellular loop that includes a signature motif (GLWXXC) and a pair of conserved cysteine residues. On the other hand, the phylogenetic relationship of the
subunits to claudin families is much lower compared with that among
subunits (15). However, the possibility exists that indeed the
family may be a subfamily of the claudin superfamily.
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Expression Profile of Subunits at Tissue and Subcellular Levels
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Tissue distribution of
subunits has been studied mainly at the mRNA level through RT-PCR1 or Northern blot analyses. In the case of some neuronal
subunits, there are additional data from in situ hybridization, immunohistochemical, and Western blot analyses. In general, the expression pattern of each
subunit varies considerably among tissues. The mRNA of
1 is primarily expressed in skeletal muscle (10, 11, 15, 16) although mild mRNA expression of
1 in other tissues has also been reported (10, 15, 16). At the protein level,
1 was detected in skeletal muscle but not in the brain or the heart (9, 19). Like
1,
6 also showed robust expression in skeletal muscle and mild expression in the other tissues (15, 16). In addition, RT-PCR results showed that the short form
6 has a different tissue distribution from that of the long form
6 (16). The analyses of neuronal
subunits (
25 and
78) showed predominant expression of their mRNA in the brain. However, in contrast to the brain-restricted expression of
3 and
5, the other neuronal
subunits are expressed in various tissues (15, 16).
2 and
8 are expressed in testis whereas the expression of
4 is in lung and prostate tissue (15, 20). Finally, the expression of
7 has been detected in various tissues (16) although a recent study suggested a brain-specific expression of
7 (17). Similarly, Western blot data from mouse brain showed specific expression of
2,
3, and
4 proteins only in neuronal tissues (6).
Regional differences of neuronal
expression within the brain have been studied at the mRNA and protein levels through RT-PCR, in situ, immunohistochemical, and/or Western blot analyses. The RT-PCR and in situ hybridization analyses of mouse brain showed highest expression of
2 in cerebellum (4, 14, 20). The
3 expression was strong in the hippocampus, cerebral cortex, amygdala, and nucleus accumbens (14, 20). In addition,
3 expression in cerebellum was reported by an in situ hybridization study (21). The
4 expression was high in the caudate putamen, olfactory bulb, and habenulae (14). The
2 and
4 expression in the cerebellum originates predominantly from the Purkinje cell layer and not from the granular cell layer (14). Likewise, the regional expression of the neuronal
proteins has been analyzed through immunohistochemistry of mouse brain, and the results are consistent, to a certain degree, with the mRNA expression patterns (6). The
2 proteins express highest in the cerebellum and cortex. The
3 protein expression levels are highest in the cortex. The
4 proteins express highest in the cortex, midbrain, hippocampus, and striatum (6). Finally, partial purification of the Ca2+ channel complex from rabbit cerebellum showed that the protein expression of
3 in cerebellum is as strong as that of the whole brain (5).
Subcellular expression of the
subunits has been studied through immunofluorescence and electron microscopy (EM) studies. Immunofluorescence studies showed that
2,
3, and
4 can go to the plasma membrane by themselves (20, 22). However, subcellular expression of
7 in the COS-7 cell was not associated with the plasma membrane (17). The EM study suggested predominant postsynaptic localization of
2,
3, and
4 and weak expression of these
subunits at the presynapse and the soma of neurons (6, 21). A recent subcellular fractionation study also supports the EM results: dominant expression of the
2 and
3 in postsynaptic membrane and far less expression in the presynaptic membrane (23).
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Protein Studies of Subunits
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Relatively less information is available about the
subunits at the protein level compared with the other Ca2+ channel subunits. The small size and high hydrophobicity of the
protein limit the choice of peptides for the development of antibodies against a
subunit that do not cross-react with the other
subunits.
The
1 subunit was found to be a 32-kDa protein (in reduced SDS-PAGE) co-purified with Ca2+ channels (Cav1.1) from rabbit skeletal muscle (8). Immunoprecipitation with antibodies specific for
11.1 and
subunit supports the association of
1 with Cav1.1 (9). Since
1 was co-purified with Ca2+ channels of skeletal muscle, there has been little doubt about the association of
1 with Cav1.1 in native tissue. However, because the neuronal
subunit was not initially co-purified with Cav2.2 (24), the association of neuronal
with Ca2+ channels has been controversial for several years since the finding of the
2 (stargazin) through the study of stargazer mice (4). However, two recent biochemical studies have shown the association of neuronal
subunits with neuronal Ca2+ channels. The association of
2 and
3 with Cav2.1 and Cav2.2 was demonstrated by co-sedimentation of
2 and
3 with neuronal Ca2+ channel subunits and by immunoprecipitation of
2 and
3 by antibodies specific for either
12.1/2 or
of Ca2+ channels (5). In this study, the molecular sizes of the
2 and
3 proteins in native tissue are reported as 38 and 34 kDa (in reduced SDS-PAGE), respectively (5). The association of
2,
3, and
4 with
12.2 was also suggested by immunoprecipitation of
12.2 by antibodies recognizing
2,
3, and
4 (6). In addition, the co-sedimentation of
2 and
3 with neuronal Ca2+ channel subunits (5) was demonstrated through partial purification of neuronal Ca2+ channels performed utilizing wheat germ agglutinin chromatography instead of heparin chromatography, which was used for initial purification of neuronal Ca2+ channels (24), suggesting a dissociation of
2 and
3 from the Ca2+ channel complex by heparin. Furthermore, a recent study with
1-
2 chimeras suggested that the first half of the
subunit has binding domain(s) to the
1 subunit of Ca2+ channels (25). The association of the other
subunits with high voltage-activated Ca2+ channels has not yet been studied. No interaction between any
subunit and low voltage-activated Ca2+ channels in native tissues has been reported.
Some neuronal
subunits (
2,
3,
4, and
8) have a PDZ binding motif (R(R/K)TTPV) at the end of the C terminus (16). The binding of some PDZ domain-containing proteins to the PDZ binding motif of
2 has been reported (21, 26, 27). Furthermore, two of the studies suggested that the binding of PSD95 to the PDZ binding motif of the
2 subunit is regulated by phosphorylation of a threonine (Thr-321) in the motif (26, 27). In addition, one of these studies also suggested an interaction between the
2 and
-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors (21). On the other hand, the association of the AMPA receptor and PSD95 with Ca2+ channels has been demonstrated in native tissue, but
2 was not essential for this association (23).
It has been shown that the
1 subunit is glycosylated (28). The glycosylation of some neuronal
subunits (
24) has been also reported (6). The N-linked glycosylation site in the first extracellular loop of the
subunit is highly conserved among all
subunits, suggesting an important functional role of the glycosylation. The glycosylation may play an important role in the association of the
subunit with the Ca2+ channel complex as shown in the study of
2
(29), in the folding of the
subunit, and/or in the targeting of proteins interacting with the
subunit. On the other hand, a recent study suggested that the glycosylation is not essential for the association of the
1 subunit with the Ca2+ channel complex (25). In addition, most of the
subunits have several potential sites for serine or threonine phosphorylation in addition to the one in the PDZ binding motif (15). Phosphorylation in these sites may be important in the function or association of the
subunit within the Ca2+ channel complex or with other proteins.
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Functional Studies of Subunits
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A relatively small number of
1 functional assays compared with that of
and
2
have been performed, which suggested mild changes in current amplitude, current kinetics, and/or voltage dependence of steady-state inactivation of the Ca2+ channels (3135). However, it has been very difficult to reach a conclusion regarding the actions of the
1 subunit as the results of the functional assays have been conflicting. Furthermore, the physiological relevance of
1 has been difficult to estimate from the functional assays because they have been performed with cardiac
1 (
11.2) or brains
1 (
12.1) rather than skeletal muscle
1 (
11.1) due to the particularly low expression of
11.1 in heterologous systems. Recently,
1 null mice have been generated by gene-targeting techniques, and it has been demonstrated that
1 has inhibitory effects on the activity of Ca2+ channels in skeletal muscle (36, 37). Two independent analyses of the
1 null mice reported an increase in current amplitude, a slowing of inactivation, and a positive shift of steady-state inactivation of Ca2+ channels in skeletal muscle as the main phenotype of the mice, indicating inhibitory effects of
1 on the functional activity of Ca2+ channels in skeletal muscle.
Similarly, there has been controversy about the function of the neuronal
subunits for some time since the finding of neuronal
subunits. However, inhibitory effects of neuronal
subunits on Ca2+ channel activity have been consistently demonstrated by three recent electrophysiological studies (5, 17, 38). Electrophysiological analyses of recombinant Cav2.1 and Cav2.2 expressed in Xenopus oocytes showed that
2 co-expression significantly decreases current amplitude (3740%) of the neuronal Ca2+ channels (5). Consistent with the
2 functional assays in the heterologous system, patch clamp analysis of stargazer mouse brain slices showed a 45% increase in the current density of high voltage-activated Ca2+ channels (38). Similarly,
7 co-expression with Ca2+ channels caused significant reduction in the Ca2+ channel currents (Cav1.2, Cav2.1, and Cav2.2).
Given that both low voltage-activated Ca2+ channels and the
subunit are implicated in the etiology of epilepsy, it has been suggested that low voltage-activated Ca2+ channels may be modulated by the
subunit. However, there have been only two functional assays of the
subunit in heterologous systems that reported a change in low voltage-activated Ca2+ channel activity by
subunits (14, 20). On the other hand, a recent electrophysiological study of stargazer mouse brain slices showed significant change in the current density and steady-state inactivation of low voltage-activated Ca2+ channels (38), suggesting that
2 loss could affect the activity of low voltage-activated Ca2+ channels as well as high voltage-activated Ca2+ channels in vivo. However, it is not clear whether the effects are direct or indirect.
As previously mentioned, the neuronal
subunits (
2,
3,
4, and
8) have a PDZ binding motif (R(R/K)TTPV) at the end of the C terminus (16). It has been suggested that the PDZ binding motif of
2 subunit binds to PSD95 and that this binding is regulated by phosphorylation of a threonine (Thr-321) (26, 27). In addition, a role of the
2 subunits on the trafficking/clustering of AMPA receptors was reported. AMPA receptor trafficking was increased by coexpression of
2 in COS7 cells (21, 39). Taken together, these studies suggest that
can increase the targeting of the AMPA receptor to the postsynapse through interaction with PSD95. Alternatively, considering the function of
2 in the fine-tuning of Ca2+ channel activity, it is possible that
2 modulates AMPA receptor trafficking by changing the intracellular concentration of Ca2+ ([Ca2+]i) in a local area of a neuron. It is known that the increase of postsynaptic [Ca2+]i is one of the prerequisites for the long term potentiation at excitatory synapses and that AMPA receptor trafficking is one of the key components for the long term potentiation (40). Accordingly, a recent study demonstrated that the change of local [Ca2+]i could regulate the lateral movement of AMPA receptors in cultured hippocampal neurons (41). Furthermore, a recent study demonstrated the association of AMPA receptors with neuronal Ca2+ channels in the postsynaptic membrane (23).
Considering the significant homology between
and claudin,
may have similar functions to claudin as a junctional protein. The claudins are cell adhesion proteins in tight junctions that are linked to membrane-associated guanylate kinase homologues (ZO-1, ZO-2, and ZO-3) through their PDZ binding domain at the end of the C terminus (42, 43). Similarly,
may function as a cell adhesion protein at the synapse through its interaction with PDZ domain-containing proteins. In addition, a recent study of
4 expression during the development of chick embryo reported that the beginning of
4 expression in neuronal tissues such as cranial ganglia and dorsal root ganglia is observed at the stage when these neuronal tissues initiate neuronal differentiation, suggesting that the
4 subunit plays a role in the development of the neuronal tissues (44).
Taken as a whole, the above mentioned results suggest that the neuronal
subunits have more than one function in the brain.
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Disorders Linked to Ca2+ Channels
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A number of human and murine mutations in Ca2+ channel subunits have been identified to be responsible for neurological disorders. In the case of human neurological disorders, mutations in the
12.1 have been associated with familial hemiplegic migraine, spinocerebellar ataxia type 6, and episodic ataxia type 2 (45). The
11.4 is associated with congenital stationary night blindness (45). A study reported a mutation of
12.1 in a patient with epilepsy and ataxia (46). Two types of mutations in the
4 subunit have also been reported in patients with epilepsy and/or ataxia (47). Recently,
1,
4, and
5 have been suggested as candidate genes for multiple sclerosis based on their loci in human chromosomes 17q23 or 17q24 (48). A recent study also reported an abnormal distribution of Cav2.2 within axons of actively demyelinating lesions of multiple sclerosis (49). In mouse models, mutations in Ca2+ channel subunits have been found through the positional cloning of mice models for absence epilepsy and/or ataxia. Four
1A mutations have been found in tottering, leaner, rolling, and rocker mice. In the case of auxiliary subunits of Ca2+ channels, the lethargic mouse has a mutation in the
4 subunit, the ducky mouse has a mutation in the
2
-2 subunit, and stargazer and waggler mice have mutations in the
2 subunit (45).
The discovery of the defective genes responsible for neurological disorders indicates that an understanding of Ca2+ channel function could lead to further comprehension of the molecular mechanisms of those neurological disorders.
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Mouse Models for Study of Subunits
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Two
1 null mice have been generated from two independent groups (36, 37). Although these mice are fertile and show no obvious phenotypic abnormalities, detailed electrophysiological analysis of L-type currents from isolated myotubes showed significant changes in Ca2+ channel activity in skeletal muscle: an increase in peak current density, a slowing of inactivation, and a positive shift of steady-state inactivation (36, 37). As previously mentioned, RT-PCR analysis suggested that
6 and
7 as well as
1 are highly expressed in skeletal muscle. The homology of
6 to
1 is higher than that of
7, and
6 shows higher expression than
7 in skeletal muscle. Therefore,
6 might be another skeletal muscle
subunit compensating the
1 loss in the
1 null mice.
The stargazer mouse has been studied as a mouse model of several neurological disorders including absence epilepsy, inner ear defects, and ataxia (51). Its recurrent spike-wave seizure associated with behavioral arrest is similar to the characteristics of human absence epilepsy. Abnormal gait of the mouse is a sign of cerebellar ataxia. Head tossing and impaired conditioned eye-blink responses are presumed to be consequences of the problem in the vestibular system and the deficit in cerebellar learning, respectively. The mutation in the stargazer mouse is the insertion of a 6-kb early transposon into the intron between exon 2 and exon 3 in the
2 gene (CACNG2) (4). Western blot and in situ hybridization analyses of stargazer brain demonstrated the absence of
2 protein expression in the mutant mouse (5, 6). Some studies on stargazer mice have suggested several possible molecular mechanisms. The increase of slowly activating inward current resembling the Ih has been proposed as one of components that contribute to the cortical hyperexcitability of the stargazer mouse (52). The mRNA and protein levels of brain-derived neurotrophic factor, a mediator of neuronal development and regulator of synaptic function, were reduced by 70% compared with those of wild-type mice in the cerebellum of stargazer mice (53, 54). Finally, studies on the stargazer mouse have shown a lack of functional AMPA receptors in cerebellar granule cells of the mouse (21, 55, 56).
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Conclusions and Perspective
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There is increasing evidence for the association of the
subunits with the Ca2+ channel complex. Eight
subunits have been identified, and phylogenical analyses have suggested that they belong to a protein family originating from a single gene. Biochemical and electrophysiological studies showing the physical and functional association of
subunits with the Ca2+ channel strongly support the idea that
is a component of the Ca2+ channel complex. On the other hand, the
2 subunit binds to PDZ domain-containing proteins and is involved in the trafficking of the AMPA receptor. Considering the number of neurological disorders in humans and/or mice linked to genes encoding Ca2+ channel subunits including the
subunit, elucidation of the mechanisms of
function will be very helpful to better understand various physiological and pathological events mediated by Ca2+ channels.
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FOOTNOTES
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* This minireview will be reprinted in the 2003 Minireview Compendium, which will be available in January, 2004. 
Partly supported by an Epilepsy Foundation predoctoral fellowship. 
Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Howard Hughes Medical Inst., University of Iowa College of Medicine, 400 EMRB, Iowa City, IA 52242. Tel.: 319-335-7867; Fax: 319-335-6957; E-mail: kevin-campbell{at}uiowa.edu.
1 The abbreviations used are: RT, reverse transcriptase; EM, electron microscopy; AMPA,
-amino-3-hydroxy-5-methyl-4-isoxazole propionate. 
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