Departments of 1 Internal Medicine and 2 Surgery, Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0682
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() |
---|
Histamine exerts multiple biological actions through one of three receptor subtypes (H1, H2, and H3). This review focuses on new developments regarding the structure and function of the H2 receptor. In addition to the important role this receptor plays in stimulating gastric acid secretion, recent studies have demonstrated that it is also involved in regulating gastrointestinal motility and intestinal secretion. The potential role of the H2 receptor in regulating cell growth and differentiation has also been added to the list of actions this biogenic amine may exert in both normal and transformed tissues. Molecular cloning of the gene indicates that it has the structural characteristics of a heptahelical G protein-linked receptor. Site-directed mutagenesis studies of this receptor reveal the presence of key amino acids within the third and fifth transmembrane domains that are critical for ligand recognition. Molecular approaches have also shed light on the structural components of the H2 receptor important in regulating desensitization and internalization. Although the H2 receptor was classically thought to couple to the adenylate cyclase pathway, recent work with the cloned receptor indicates that it can also activate the phosphoinositide signaling cascade through an independent G protein-dependent mechanism. The novel observation that histamine may stimulate c-fos gene expression lends further support to the possible role of this receptor in regulating cell growth and differentiation.
biogenic amine; G protein; signal transduction
![]() |
HISTAMINE |
---|
Histamine [2-(4-imidazolyl)ethylamine] was isolated from ergot extracts over 80 years ago by Dale and Laidlaw (20). These insightful investigators hypothesized that this biogenic amine mediated vascular dilatation and smooth muscle contraction observed during anaphylaxis. Histamine is synthesized in a wide variety of cells throughout the body, including mast cells, basophils, platelets, enterochromaffin-like cells, endothelial cells, and neurons, through histidine decarboxylation (70). The enzymes that mediate decarboxylation of L-histidine include L-dopa decarboxylase and histidine decarboxylase, which plays an important role in the gastrointestinal tract. Initially hypothesized to function primarily as a mediator of inflammation, histamine has subsequently been found to exert a host of biological actions, including regulation of gastric acid secretion. The interesting observation that histamine synthesis can be induced and made available in an unstored diffusible form in tissues undergoing rapid growth or repair suggests additional physiological roles for this biogenic amine (41, 45).
![]() |
HISTAMINE RECEPTOR SUBTYPES |
---|
An extensive review of histamine receptor subtypes is beyond the scope of this article. The reader is referred to several excellent recent publications for further details on the subject (6, 7, 41, 51).
The potential involvement of histamine as a mediator of inflammation was the impetus behind the development of pharmacological tools useful in blocking its actions. Bovet and Staub (15) developed the first in a series of compounds that successfully blocked the action of this biogenic amine on vascular dilation and smooth muscle contraction observed during an anaphylactic response. These drugs were termed antihistamines (subsequently shown to be H1 antagonists). The insightful observation by Ash and Schild (8) that traditional antihistamines did not block the action of this agent on cardiac muscle and gastric secretion, coupled with studies examining the effect of different agonists, led these investigators to postulate that histamine exerted its biological actions through at least two different types of receptors. This hypothesis was confirmed when Black and co-workers (12, 13) developed several novel compounds capable of blocking the stimulatory effects of histamine on guinea pig right atrium and gastric acid secretion. These compounds, which revolutionized the treatment of acid peptic disorders, were classified as H2 receptor antagonists. More recently, a third type of histamine receptor was identified by Arrang and colleagues (5). This novel receptor subtype (H3) regulates histamine synthesis and release from both the central and peripheral nervous system, as well as from several nonneural elements (11, 53, 75).
![]() |
BIOLOGICAL ACTIONS MEDIATED VIA THE H2 RECEPTOR |
---|
Development of highly selective H2 receptor agonists [4-(S)-methylhistamine, dimaprit, amthamine, and impromidine] and antagonists (burimamide, cimetidine, ranitidine, tiotidine, and famotidine) has greatly facilitated characterization of the multiple biological actions regulated by this amine receptor. It is involved in a host of physiological actions, including relaxation of airway (26) and vascular smooth muscle (10, 68), regulation of chronotropic and inotropic effects in right atrial and ventricular muscle, respectively, inhibition of basophil chemotactic responsiveness (56), inhibition of mitogen-mediated immunocyte proliferation via induction of suppressor T cells (74), and differentiation of promyelocytic leukemic cells to mature granulocytes (76). Several novel observations have recently been made regarding H2 receptor action in the gastrointestinal tract. Below is a brief summary of these.
The positive impact of H2 receptor
antagonists in the therapy of acid peptic disorders complements a large
body of in vivo and in vitro studies (47, 83) demonstrating the
important role of this receptor in regulating gastric acid secretion.
Despite this, the concept of histamine directly regulating parietal
cells was questioned by Mezey and Palkovits (58). This
controversial issue was recently revisited by Diaz and
co-workers (24). Using in situ hybridization histochemistry and
autoradiography with a highly selective
H2 receptor radioligand
(125I-aminopotentidine),
Diaz and co-workers (24) detected a specific signal for
H2-specific gene transcripts only
within parietal cells of the gastric epithelium. The discrepant results
obtained by these two investigative teams may be in part due to the
less-sensitive oligonucleotide probes used by the former group compared
with the highly specific
H2-receptor antisense riboprobe
used by the latter. It therefore appears that
H2 receptors are definitely localized on gastric parietal cells, as initially postulated by multiple investigators. This does not exclude the possibility that
receptors for this amine are also located on immunocytes. Many
subsequent studies have continued to support the direct effect of
histamine on parietal cell function. One recent report demonstrated that occupation of the parietal cell
H2 receptor induces expression of
the gastric
H+-K+-adenosinetriphosphatase
-subunit (88).
Histamine H2 receptors also appear to play a role in the regulation of gastrointestinal motility. The complex interplay between histamine H1 and H2 receptors on intestinal smooth muscle function was recently demonstrated by Morini and co-workers (62). In a series of elegant experiments in isolated longitudinal smooth muscle cells from guinea pig intestine, it was demonstrated that H1 receptors, which modulate smooth muscle contraction in a Ca2+-dependent manner, coexist in a complementary manner with H2 receptors that induce adenosine 3',5'-cyclic monophosphate (cAMP)-dependent relaxation. These observations are particularly relevant in view of the defined neuronal pool of histamine, which is subject to release by multiple factors (39, 69). Moreover, mast cells, which are a rich source of histamine, are present in the circular and longitudinal muscle layers of the intestine (70). These results suggest that antigen- or cytokine-mediated mast cell degranulation may directly impact gastrointestinal motility.
Histamine H2 receptors also appear
to play a role in regulating intestinal secretion. Histamine was
observed to inhibit prostaglandin E2-stimulated duodenal epithelial
bicarbonate secretion through what appears to be an
H2 receptor located on enteric
neurons (42). This observation adds another pathway (in addition to
stimulating gastric acid secretion) through which histamine can induce
duodenal mucosal damage. Neuronal histamine also appears to be involved in the regulation of colonic secretion (19, 29-31). In a series of
experiments using strips of guinea pig colon, Cooke and co-workers (19)
revealed that histamine-mediated activation of
H2 receptors led to an increase in
short-circuit current and
Cl secretion by stimulating
cholinergic neurons that utilize muscarinic and nicotinic synapses and
by activating vasoactive intestinal polypeptide
(VIP)-ergic pathways. Together, these findings may in part explain the
motility and secretory abnormalities associated with intestinal
inflammation.
An intriguing and potentially exciting role for the H2 receptor has been in the regulation of cell proliferation. Human mammary (21) and gastric carcinoma cells (MKN-45) (3) and several human melanoma cell lines express H2 receptors (95, 106). More recently, Watson et al. (103) demonstrated that histamine can stimulate the proliferation of two gastric carcinoma cell lines (MKN-45, MKN-45G) in an H2-specific fashion. The interesting observation by Tonnesen and co-workers (90) that cimetidine improved survival in patients with gastric cancer adds greater potential significance to the role of histamine in cell growth. Despite these interesting observations, some have failed to detect a significant proliferative effect of histamine in several experimental models tested (16, 107). The mechanism by which histamine may regulate cell proliferation is addressed later in this review.
![]() |
H2 RECEPTOR STRUCTURE |
---|
Early pharmacological studies demonstrated that the biologically active form of histamine was a monocation (105) and that tautomerism of the imidazole ring was important for binding of histamine to the H2 receptor subtype. Despite these important observations, little was known regarding the structure of this biogenic amine receptor. Attempts at purifying the receptor protein were fraught with several difficulties, including low binding affinity (72). Determination of the putative structure of this receptor was recently obtained through molecular cloning.
The gene encoding the histamine H2 receptor was not isolated at the DNA level or cloned until 1990, years after the development of therapeutic antagonists of this receptor and their widespread application to clinical medicine for the treatment of acid peptic disorders (33). The isolation of the sequence was accomplished by applying the technique of polymerase chain reaction (PCR) using degenerate oligonucleotides based on homologous regions of other seven-transmembrane G protein-linked receptors (7TM GPCRs), the sequences of which were known at the time. This technique had first been successfully used by Libert et al. (54) to clone the thyrotropin receptor from thyroid tissue. Degenerate PCR oligonucleotide primers corresponding to conserved sequences within the third and sixth transmembranes of 7TM GPCRs were used to clone the H2 receptor. Although these primers were identical to those used in the experiments of Libert et al. (54), the key modification was the use of RNA rich in histamine H2 receptor transcripts as the reaction substrate. Using RNA extracted from 70% enriched gastric parietal cells as the target for the PCR, a novel partial receptor sequence was isolated. The DNA fragment was recognized as a partial receptor fragment from its sequence homology to other 7TM GPCRs and from its hydropathy pattern, which is compatible with such a structure. The novel sequence was investigated further by isolating a full-length DNA sequence from a canine genomic lambda EMBL 3 phage library. The use of a genomic library instead of a cDNA library was based on the premise that many GPCRs are intronless within their coding regions (48). A single genomic clone was obtained that contained a 1,080-base pair open reading frame and a deduced amino acid sequence of 360 amino acids. The putative structure of the H2 receptor is shown in Fig. 1. It is important to recognize that the use of degenerate oligonucleotides based on homologous regions of known molecules to isolate other similar molecules within a family is an indirect cloning approach. Characteristically, this approach results in the isolation of both known and novel sequences. Although it appeared clear that the full-length sequence isolated from the canine genomic library represented a 7TM GPCR from its sequence homology to that class of receptor, initially the novel clone represented an "orphan" receptor because it lacked an identified ligand. In other words, it could have been any of a myriad of receptors present in the gastric mucosa.
|
Analysis of the "orphan" provided two key pieces of information
that led to the hypothesis that it might be the histamine H2 receptor. The first was that
Northern blot analysis of different elutriated fractions of gastric
mucosal cells revealed that the highest level of receptor expression
was in the RNA derived from the parietal cell fraction. The second was
a sequence similarity between the orphan receptor and the biogenic
amine receptors that had already been cloned. An Asp residue present in
the third transmembrane of those cloned biogenic amine receptors and
previously implicated as a counteranion to the cationic ethylammonium
moiety of their biogenic amines was present in the sequence of the
novel parietal cell receptor (85, 87). In addition, there was a
remarkable conservation of amino acid sequence within the
NH2 terminus and COOH terminus of
the third intracytoplasmic loop of the
2-adrenergic receptor and the
orphan parietal cell receptor (amino acids Ala-Lys-Arg in the
NH2 terminus and
Glu-His-Lys-Ala in the COOH terminus). These portions of
the third intracytoplasmic loop had already been identified as areas
involved in coupling to the stimulatory G protein,
Gs, in the case of the
2-receptor (66, 84). These clues led to the formulation of the question, What is a biogenic amine
receptor highly expressed by the parietal cell that couples to
Gs? The answer, the histamine
H2 receptor, was verified by expressing the orphan receptor in a mammalian cell line. Cells transfected with the receptor responded to histamine by an increase in
intracellular cAMP and demonstrated an antagonist profile
characteristic of the H2 subtype
of histamine receptor.
Since that initial report, genomic sequences of the human (34), rat (73), and guinea pig (94) histamine H2 receptor have been reported. Certainly, for the purposes of receptor expression, the open reading frame of the intronless histamine H2 receptor gene is completely adequate. However, it is worth noting that a complete cDNA has never been reported for this receptor.
![]() |
MOLECULAR BASIS FOR THE INTERACTION OF HISTAMINE WITH THE HISTAMINE H2 RECEPTOR |
---|
As with other 7TM G protein-coupled biogenic amine receptors, histamine
is thought to bind within a pocket formed by the transmembrane -helixes of the histamine H2
receptor. In the case of the small lipid-soluble biogenic amines, this
pocket is thought to exist within the lipid bilayer of the cell
membrane (91). The agonist, in this instance histamine, binds to
receptor residues within this pocket by various ionic and nonionic
molecular interactions. The exact receptor residues involved in the
binding of histamine to the H2
receptor have been investigated by site-directed mutagenesis (35).
Again, this work relied heavily on analogy to the ground-breaking work
on the
2-adrenergic receptor. A
third-transmembrane Asp (17 amino acids proximal to the canonical
Asp-Arg-Tyr sequence present at the
NH2 terminus of the second
intracytoplasmic loop of all biogenic amine receptors) had already been
identified in the
2-adrenergic
and the m1-muscarinic
acetylcholine receptors to be crucial to the binding of those agonists
to their receptors (28, 85, 87). Two Ser residues within the fifth
transmembrane of the
2-adrenergic receptor had also
been identified to be sites that hydrogen bonded with the hydroxyl
groups of the adrenergic agonists (85, 86). Although these
fifth-transmembrane Ser residues were absent in the histamine
H2 receptor, it was noted that an
Asp residue and a Thr residue were somewhat similarly situated. It was
recognized that these residues had the potential to interact with the
imidazole ring of histamine via proton transfer and hydrogen bonding.
Site-directed mutagenesis of the receptor residue
Asp117 led to a total loss of
agonist-stimulated cAMP generation and [3H]tiotidine binding.
Although these data are consistent with the key role of this amino acid
in ligand binding, the total loss of functional activity and absence of
available antibody in the studies leaves room for potential criticism
that this mutation may have induced changes that prevented the receptor
protein from inserting in the cell membrane. Nonetheless, these data
are consistent with similar results that demonstrated the importance of
a corresponding third-transmembrane Asp in the binding and activation
of adrenergic and muscarinic receptors.
Mutation of fifth-transmembrane amino acids Asp186 to Ala and Thr190 to Ala either alone or simultaneously did not abolish the ability of histamine to generate cAMP but markedly decreased its efficacy. Interestingly, Asp186 was found to be essential for [3H]tiotidine binding; however, cimetidine could still bind this receptor mutant, as evidenced by its ability to partially block histamine-stimulated cAMP. This highlights the fact that antagonists may not bind identical receptor residues. Despite the recognized limitations of mutagenesis studies, the results fit remarkably well with a three-site theory for the interaction of histamine with its receptor proposed by Weinstein et al. (105) in 1976. According to this pharmacologically derived model, the positively charged ethylammonium side chain of histamine would bind to a negatively charged receptor residue. (Many years later in the referenced mutagenesis study, this receptor residue was identified as the third-transmembrane Asp117). The subsequent decrease in charge within the imidazole ring would result in a tautomeric shift of double bonds within that ring that would subsequently allow both nitrogens of the ring to hydrogen bond with two other receptor residues (identified by mutagenesis studies to both be in the fifth transmembrane). For example, Thr190 would act as a proton donor and Asp186 as a proton acceptor (Fig. 2). However, because the ionization state of the fifth-transmembrane Asp186 is unknown, either residue in principle could act as a proton donor or acceptor. Later refinements of this model have been developed to explain the agonist activities of nontautomeric histamine H2 receptor agonists (25). Finally, it is worthy of note that although three-dimensional computer-generated models of 7TM GPCRs have become an important adjunctive tool for drug development, such a model has not yet been reported for the histamine H2 receptor.
|
Comparison of the results of similar mutagenesis studies of the histamine H1 receptor with those of the H2 receptor is further illustrative of histamine binding to both of these receptors. Site-directed mutagenesis of analogous third- and fifth-transmembrane residues of the histamine H1 receptor has been performed (52, 65). Somewhat surprisingly, these two receptors share a rather low sequence homology for two receptors with the same ligand (43% nucleotide sequence identity and 33% amino acid similarity). Similar to the H2 histamine receptor, the third-transmembrane Asp of the H1 receptor has been found to be essential for histamine binding and binding of the H1 antagonist mepyramine. Presumably for both histamine H1 and H2 receptors this Asp acts as a counteranion to the cationic ethylammonium group of histamine. In the sequence of the histamine H1 receptor, fifth-transmembrane residues Thr194 and Asn198 lie in corresponding positions to the crucial Asp186 and Thr190 of the histamine H2 receptor. However, mutagenesis of these H1 receptor residues only identified Asn198 as essential for histamine binding. Furthermore, although this receptor residue was involved in binding histamine, it was not required for full affinity of the agonist 2-(3-bromophenyl)histamine and nonimidazole H1 receptor agonists (2-pyridylethylamine and 2-thiazolylethylamine). In addition, neither fifth-transmembrane residue was necessary for binding of the H1 antagonist mepyramine. Some differences between the two receptors are not unexpected, because different structural demands should exist, as evidenced by the development of selective histamine H1 and H2 receptor agonists.
Further development of similarity in binding requirements of
2-adrenergic and the histamine
H2 receptors noted above led to
the construction of a "hybrid" receptor (23). This receptor hybrid was designed to be a cross between the histamine
H2 and
2-adrenergic receptors and was
based on the sequence of the histamine H2 receptor. The
third-transmembrane Asp utilized by both agonists to bind to their
receptors was already present. Within the fifth transmembrane,
Asp186 of the histamine
H2 receptor was mutated to the
neutral amino acid Ala and Gly187
to Ser. This arrangement mimicked the placement of the first of two
fifth-transmembrane Ser present in the
2-receptor. Conceptually, the
second hydroxyl side chain would be provided by
Thr190, already present in the
sequence of the histamine H2
receptor. Interestingly, this experiment resulted in a unique
bifunctional receptor. Both histamine and epinephrine were capable of
generating intracellular cAMP at this hybrid receptor. Furthermore,
either agonist response could be blocked by propanolol or cimetidine.
It is important to realize that although the above mutagenesis studies of the histamine H2 receptor provide some insight into the binding of the agonist histamine and the antagonists tiotidine and cimetidine, the exact receptor residues involved in the molecular interactions of the widely used clinical antagonists (cimetidine, ranitidine, and famotidine) have not been investigated using similar techniques.
![]() |
DOWNREGULATION OF HISTAMINE H2 RECEPTOR FUNCTION |
---|
Desensitization of endogenous histamine H2 receptors has been noted in the human leukemia cell line HL-60 and human adenocarcinoma cell line MKN-45 (4, 44). Rapid homologous and heterologous desensitization has been observed in the case of the HL-60 cell. In the case of the MKN-45 cell line, a cAMP-independent homologous desensitization was observed, but heterologous desensitization was absent. In both cases the mechanism(s) involved remains incompletely understood.
The sequence of the histamine H2
receptor does not contain a consensus protein kinase A phosphorylation
site (double Arg residues NH2-terminal to either two or
three Ser residues followed by a Lys) (14). This observation is
consistent with the findings of several studies (4, 50). Five potential
consensus phosphorylation sites for protein kinase C (PKC) (Ser or Thr
located two positions NH2-terminal
to a Lys or Arg) are found in the intracytoplasmic loops of the
histamine H2 receptor, although
these have not been studied in a systematic manner to determine whether
they are actually targets of that kinase (14). It is presently unknown
whether G protein receptor kinases are involved in the desensitization process, but by analogy to the closely related
2-adrenergic receptor and the
widespread use of these kinases by 7TM GPCRs, it is at least
conceivable that such an interaction occurs in the case of the
histamine H2 receptor (40).
Another aspect of 7TM GPCR downregulation that has been studied is the
phenomenon of internalization or sequestration (78). Using an
epitope-tagged receptor and immunofluorescence microscopy,
agonist-induced endocytosis of the histamine
H2 receptor has been demonstrated
(78). Thus the histamine H2
receptor appears to share at least some of the regulatory features
common among the 7TM GPCRs.
![]() |
PHENOMENON OF INVERSE AGONISM AND UPREGULATION OF THE HISTAMINE H2 RECEPTOR |
---|
Recently it has been noted that in certain model systems, some GPCRs have increased basal agonist-independent receptor activity that can be inhibited by certain antagonists but not others (60). Antagonists that induce basal inhibition have been termed inverse agonists. This phenomenon has led to the development of a new pharmacological concept of antagonism. According to this new concept a continuum of ligands might be found between the two extremes of full inverse agonist and full agonist. The "classic" neutral antagonist would hold middle ground in this scheme, with partial inverse agonists and partial agonists to either side. Recently it has been shown that certain commonly used H2 antagonists, cimetidine and ranitidine, display inverse agonism at the H2 receptor (79). In contrast, this phenomenon is not observed with the prototype histamine H2 antagonist burimamide, which is considered a "neutral" antagonist according to this new concept. In addition, it has been observed in the case of the histamine H2 receptor that antagonists displaying inverse agonism also cause upregulation of the number of receptors per cell. This may have important implications for medical therapy and may be responsible for the clinical observation that H2 receptor antagonists become less effective with time and that hypersensitivity to histamine occurs after cessation of treatment.
![]() |
HISTAMINE H2 RECEPTOR GENE REGULATION |
---|
The transcription initiation site of the histamine
H2 receptor has never been
determined for the gene in any species. Nucleotide sequence analysis of
the portion of the human histamine
H2 receptor gene upstream from its
start codon reveals the presence of four cAMP response elements, three
GATA motifs, three
AP2 sites, four palindromes, and two direct repeats (63). No TATA box-like sequence is
found in the human or canine genes, although one appears to be present
in the sequence of the rat gene (73). Only one study has examined the
regulatory elements within 1.8 kilobases upstream of the histamine
H2 receptor start codon (63).
Fragments of the upstream portion of the human gene were coupled to a
luciferase reporter and expressed in the human gastric cancer cell line
MKN-45. Two regions were identified within the ranges of 61 to
278 and
611 to
1202 upstream that increased
luciferase activity and therefore might contain a promoter or enhancer
element. The region
1203 to
1773 corresponded to an
inhibition of luciferase activity in this model system, suggesting that
this segment might contain a repressor or silencer element.
Although it has been determined that the histamine H2 receptor is present on human chromosome 5 by genomic Southern blot, a more exact chromosomal localization has not been performed (94). Because the site of the murine gene locus has not been determined either, no correlation of this receptor with any presently mapped human or murine abnormalities can be made. Interestingly, polymorphisms do exist within the sequence of the histamine H2 receptor (67). Recently, six allelic variants were described. None of these result in a premature stop codon that might lead to a truncated nonfunctional receptor, but three do exist in the third intracellular loop, a domain known to be important to G protein coupling. Hopefully, future studies will examine whether these variations cause any functional changes in ligand binding or signal transduction. It also remains to be determined if these variants are responsible for or associated with any disease states.
![]() |
H2 RECEPTOR-MEDIATED SIGNAL TRANSDUCTION |
---|
As outlined previously, the physiological effects attributed to the
H2 receptor are broad in scope and
importance. Its activation leads to stimulation of cAMP formation in a
number of systems, including brain slices (1), stomach mucosal cells
and glands (9, 17), canine fat cells (36), heart myocytes (104), vascular smooth muscle (41), basophils (56), and neutrophils (41). A
significant body of experimental data suggests that the capability of
histamine to stimulate cAMP formation is through direct activation of
adenylate cyclase (41) via a guanine nucleotide-dependent mechanism
(43, 46). Activation of the histamine
H2 receptor has also been
associated with several additional signal transduction events. These
include stimulation of phospholipid methylation in rat mast cells (89),
an increase in the slow inward
Ca2+ current in guinea pig
ventricular myocytes via the effect of this ligand on cAMP formation
(41), inhibition of
Cl-mediated
K+ conductance in hippocampal
pyramidal cells (38), and stimulation of intracellular
Ca2+
([Ca2+]i)
mobilization in a human lymphocytic cell line (HL-60) (61) and in
gastric parietal cells (18). It has also been demonstrated that the
cloned rat H2 receptor can lead to
inhibition of phospholipase A2
(93).
The finding that histamine could lead to both an increase in cAMP and [Ca2+]i in gastric parietal cells and HL-60 cells suggested either that it was acting on two different subclasses of H2 receptors, each linked to separate pathways, or that it was activating a single class of H2 receptor linked to both signaling systems (Fig. 3). Experiments with the cloned H2 receptor confirmed the direct linkage of a single receptor to both the adenylate cyclase and phosphoinositide signaling pathways. Multiple reports demonstrated that single receptors may be associated with more than one G protein and thus to multiple intracellular signaling systems (2, 37, 71, 96, 97). H2 receptor dual signaling has several unique properties compared with other receptors that regulate multiple pathways. In contrast to the m1 cholinergic receptor, which leads to activation of adenylate cyclase indirectly through stimulation of the phosphoinositide/calmodulin cascade (27), the H2 receptor activates each signaling system in a direct manner. In comparison to the tachykinin and luteinizing hormone receptors (57, 97), which require different ligand concentrations to activate either Ca2+- or cAMP-dependent signaling systems, the concentration of histamine required for stimulating both systems is identical. Despite these provocative observations, the mechanism by which one receptor links to multiple effectors and the factors involved in regulating the plurality of receptor-mediated signaling remain unknown (59).
|
Although initial studies with the cloned
H2 receptor suggested that it can
couple to both adenylate cyclase and phosphoinositide second messenger
systems via independent pathways (22), the level at which this
divergence in signaling occurs was not clear until recently. Efforts to
characterize the G proteins responsible for mediating
H2 receptor dual signaling have
led to interesting and somewhat discrepant results (49, 99).
Histamine-induced cAMP generation and membrane phosphoinositide
turnover were insensitive to pertussis toxin, suggesting that members
of the
Gi/Go
family of GTP-binding proteins were not involved in histamine
signaling. In contrast, cholera toxin pretreatment inhibited
histamine-stimulated inositol phospholipid turnover and
[Ca2+]i
(22). The effect of cholera toxin was independent of its ability to
activate adenylate cyclase, since prolonged stimulation of this pathway
with forskolin failed to reproduce these findings. In a recent series
of experiments, the most likely candidate G proteins involved in
H2 receptor signaling
(Gs and
Gq) were explored (49, 99).
Immunoneutralization experiments using isolated membranes obtained from
canine gastric parietal cells and transfected HEPA cells demonstrated
that histamine increased adenylate cyclase via
Gs. Of interest, the
stimulatory effect of histamine on phospholipase C (PLC) activity was
dependent on the presence of GTP, inhibited by pretreatment of cells
with cholera toxin, but unaffected by pertussis toxin or antibodies
specific for Gs
,
Gq
, or common
-subunits
(99). On the basis of these results it appeared that the
H2 receptor activated both the
adenylate cyclase and phosphoinositide signaling cascade via separate
GTP-dependent mechanisms. The issue that still remains unclear is the G
protein involved in histamine-mediated PLC stimulation. Kühn and
co-workers (49) recently confirmed that the
H2 receptor can activate both adenylate cyclase and PLC in baculovirus-infected Sf9 cells and COS
cells transfected to express the
H2 receptor. These investigators also demonstrated that the stimulatory effect of histamine on PLC was
significantly enhanced when DNAs corresponding to
q,
11,
12,
14, or
15 were cotransfected into COS
cells transfected with the H2
receptor. Finally, it was demonstrated that both
H1 and
H2 receptors led to
[
-32P]GTP
azidoanilide labeling of
q and
11. Although these data are
compelling evidence demonstrating that the
H2 receptor can activate
Gq, they do not explain why
cholera toxin pretreatment abolishes the ability of histamine to
stimulate PLC. Moreover, functional assays with blocking antibodies
were not performed in this system. Therefore it is plausible that the
H2 receptor can couple to
additional, yet to be defined G proteins that are linked to PLC
activation.
Several fundamental issues regarding
H2 receptor dual signaling remain
unclear. The structural requirements of the receptor required for dual
signaling are not fully elucidated. One recent report demonstrates that
the COOH-terminal tail plays a role in signal transduction and receptor
downregulation (80). In a series of preliminary studies with synthetic
receptor-based peptides and
2-adrenergic/H2
chimeric receptors, it appears that segments of the second and third
intracellular loops and the COOH-terminal tail couple in a differential
manner to separate G proteins (98, 101). Although the physiological
importance of H2 receptor dual signaling has not been established (see below), a recent report suggests that there is interaction between the phosphoinositide and
adenylate cyclase pathways, leading to both sensitizing and desensitizing effects on histamine signaling (32).
![]() |
H2 RECEPTOR SIGNALING AND CELL GROWTH |
---|
Although H2 receptor-mediated regulation of cellular events has always been attributed to stimulation of adenylate cyclase, the simultaneous coupling of this receptor to the phosphoinositide second messenger system adds another potential pathway through which this biogenic amine may lead to a biological response. In studies by Lungstrom and Chew (55) it appears that histamine-mediated increases in cultured parietal cell [Ca2+]i were not directly involved in secretion (55). Therefore the question arises as to what is the potential role for H2 receptor-mediated stimulation of the phosphoinositide cascade. This question is especially important in view of the close association between cell proliferation/cell differentiation and activation of the PLC-regulated second messenger system (64, 77). The identification of the histamine H2 receptor on the human gastric carcinoma cell line MKN-45 (3), the observation that ranitidine (H2 selective antagonist) can lead to regression of melanoma nodules in a patient with this devastating disease (81), the presence of histamine H2 receptors on human melanoma cells (95, 106), and the finding that activation of this receptor leads to functional differentiation of human HL-60 promyelocytes (76) suggest that the H2 receptor may be involved in cellular growth and differentiation. Because of the intriguing but controversial data suggesting that the histamine H2 receptor may be involved in regulating cell proliferation, it was recently explored whether this biogenic amine could regulate cell growth in HEK cells (human embryonic kidney cells) stably transfected with the H2 receptor (100). Of interest, histamine increased [3H]thymidine incorporation into transfected HEK-293 cells in a dose-dependent and cimetidine-sensitive fashion to a maximal stimulatory effect comparable to the action of epidermal growth factor. Moreover, H2 receptor occupation led to induction of the protooncogene c-fos via activation of the serum response element. The stimulation of cell growth and the induction of c-fos were cAMP independent but PKC dependent (102). These intriguing preliminary results lend credence to the ability of this receptor to regulate cell proliferation and to do so in part via its ability to stimulate the phosphoinositide/PKC signal transduction cascade.
![]() |
CONCLUSION |
---|
![]() ![]() ![]() ![]() |
---|
The last several decades have witnessed a steady increase in our understanding of the multiple physiological roles of the histamine H2 receptor. Initially thought to regulate a limited number of targets such as contractile activity of the heart and gastric acid secretion, it is now evident that a broader range of biological actions extending from cell differentiation and proliferation to gastrointestinal motility are also sites of H2 receptor activity. Insights into the structural requirements for ligand recognition and receptor regulation have been achieved through the application of molecular and biochemical tools. The ability of this receptor to activate multiple G proteins fits into the complex paradigm of cross-talk between signaling pathways that is now being observed for multiple heptahelical receptors. Although many discoveries have been made regarding histamine H2 receptor biology, questions concerning structural requirements for ligand recognition, receptor sites important for affinity states, gene regulation of this important receptor, and the potential role of this biogenic amine receptor in cell growth yet remain.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Patricia Richards for typing this manuscript.
![]() |
FOOTNOTES |
---|
This work was supported by National Institutes of Health Grants RO1-DK-47434 and P30-DK-34933 (from the University of Michigan Gastrointestinal Peptide Research Center). I. Gantz is the recipient of a Department of Veterans Affairs Merit Review Award.
Address for reprint requests: J. Del Valle, Div. of Gastroenterology, Univ. of Michigan, 6520 MSRBI Box 0682, Ann Arbor, MI 48109-0682.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() |
---|
1.
Al-Gadi, M.,
and
S. J. Hill.
The role of calcium in the cyclic AMP response to histamine in rabbit cerebral cortical slices.
Br. J. Pharmacol.
85:
877-888,
1985[Abstract].
2.
Arai, H., and I. F. Charo. Differential regulation
of G-protein mediated signaling by chemokine receptors.
J. Biol. Chem. 271, Suppl. 36: 21814-21819, 1996.
3.
Arima, N.,
Y. Yamashita,
H. Nakata,
A. Nakamura,
Y. Kinoshita,
and
T. Chiba.
Presence of histamine H2-receptors on human gastric carcinoma cell line MKN-45 and their increase by retinoic acid treatment.
Biochem. Biophys. Res. Commun.
176:
1027-1032,
1991[Medline].
4.
Arima, N.,
Y. Kinoshita,
A. Nakamura,
Y. Yamashita,
and
T. Chiba.
Homologous desensitization of histamine H2 receptors in the human gastric carcinoma cell line MKN-45.
Am. J. Physiol.
265 (Gastrointest. Liver Physiol. 28):
G987-G992,
1993
5.
Arrang, J. M.,
M. Gargarg,
and
J. C. Schwartz.
Auto-inhibition of brain histamine release mediated by a novel class (H2) of histamine receptor.
Nature
302:
832-837,
1983[Medline].
6.
Arrang, J. M.
Pharmacological properties of histamine receptor subtypes.
Cell. Mol. Biol. (Oxf.)
40:
273-279,
1994.
7.
Arrang, J.-M.,
G. Drutel,
M. Garbarg,
M. Ruat,
E. Traiffort,
and
J.-C. Schwartz.
Molecular and functional diversity of histamine receptor subtypes.
Ann. NY Acad. Sci.
757:
314-323,
1995[Medline].
8.
Ash, A. S. F.,
and
H. O. Schild.
Receptors mediating some actions of histamine.
J. Pharmacol. Exp. Ther.
27:
427-439,
1966.
9.
Batzri, S.,
and
J. D. Gardner.
Cellular cyclic AMP in dispersed mucosal cells from guinea pig stomach.
Biochim. Biophys. Acta
541:
181-189,
1978[Medline].
10.
Beaven, M. A.
Factors regulating availability of histamine at tissue receptors.
In: Pharmacology of Histamine Receptors, edited by C. R. Ganellin,
and M. E. Parsons. Bristol, UK: Wright, 1982, p. 103-145.
11.
Bertaccini, G., and G. Coruzzi. An update on histamine
H3 receptors and gastrointestinal
functions. Dig. Dis. Sci. 40, Suppl. 9: 2052-2063, 1995.
11a.
Birdsall, N. J. M.
Cloning and structure: function of the H2 histamine receptor.
Trends Physiol. Sci.
12:
9-10,
1991.
12.
Black, J. W.,
W. A. M. Duncan,
C. J. Durant,
C. R. Ganellin,
and
E. M. Parsons.
Definition and antagonism of histamine H2-receptors.
Nature
236:
385,
1972[Medline].
13.
Black, J.
Reflections on the analytical pharmacology of histamine H2-receptor antagonists.
Gastroenterology
105:
963-968,
1993[Medline].
14.
Blake, A. D.,
R. A. Mumford,
H. V. Strout,
E. E. Slater,
and
C. D. Strader.
Synthetic segments of the mammalian AR are preferentially recognized by cAMP-dependent protein kinase and protein kinase C.
Biochem. Biophys. Res. Commun.
147:
168-173,
1987[Medline].
15.
Bovet, D.,
and
A. M. Staub.
Action protectrice des éthers phénoliques au cours de l'intoxication histaminique.
C. R. Soc. Biol.
124:
547-549,
1937.
16.
Brenna, E.,
H. G. P. Swarts,
C. H. W. Klaassen,
J. J. H. H. M. dePont,
and
H. L. Waldum.
Evaluation of the trophic effect of long-term treatment with the histamine H2 receptor antagonist loxtidine on rat oxyntic mucosa by differential counting of dispersed cells.
Gut
35:
1547-1550,
1994[Abstract].
17.
Chew, C. S.,
G. Sachs,
G. Hersey,
and
T. Berglindh.
Histamine responsiveness of isolated gastric glands.
Am. J. Physiol.
238 (Gastrointest. Liver Physiol. 1):
G312-G320,
1980
18.
Chew, C. S.
Cholecystokinin, carbachol, gastrin, histamine, and forskolin increase [Ca2+]i in gastric glands.
Am. J. Physiol.
250 (Gastrointest. Liver Physiol. 13):
G814-G823,
1986[Medline].
19.
Cooke, H. J.,
Y.-Z. Wang,
R. Reddix,
and
N. Javed.
Cholinergic and VIP-ergic pathways mediate histamine H2 receptor-induced cyclical secretion in the guinea pig colon.
Am. J. Physiol.
268 (Gastrointest. Liver Physiol. 31):
G465-G470,
1995
20.
Dale, H. D.,
and
P. D. Laidlaw.
The physiological action of iminazolyl-ethylamine.
J. Physiol. (Lond.)
41:
318-344,
1910.
21.
Davio, C. A.,
G. P. Cricco,
N. Andrade,
R. M. Bergoc,
and
E. S. Rivera.
H1 and H2 histamine receptors in human mammary carcinomas.
Agents Actions
38 (Special Conference Issue):
C172-C174,
1993.
22.
Del Valle, J.,
L. Wang,
I. Gantz,
and
T. Yamada.
Characterization of H2 histamine receptor: linkage to both adenylate cyclase and [Ca2+]i signaling systems.
Am. J. Physiol.
263 (Gastrointest. Liver Physiol. 26):
G967-G972,
1992
23.
Del Valle, J.,
I. Gantz,
L. Wang,
Y.-J. Guo,
G. Munzert,
T. Tashiro,
Y. Konda,
and
T. Yamada.
Construction of a novel bifunctional biogenic amine receptor by two point mutation of the H2-histamine receptor.
Mol. Med.
1:
280-286,
1995[Medline].
24.
Diaz, J., M. L. Vizuete, E. Traiffort, J. M. Arrang, M. Ruat, and J. C. Schwartz. Localization of the
histamine H2 receptor and gene
transcripts in rat stomach: back to parietal cells.
Biochem. Biophys. Res. Commun. 198, Suppl. 3: 1195-1202, 1994.
25.
Eriks, J. C.,
H. Van der Goot,
and
H. Timmerman.
New activation model for the histamine H2 receptor, explaining the activity of the different classes of histamine H2 receptor agonists.
Mol. Pharmacol.
44:
886-894,
1993[Abstract].
26.
Eyre, P.,
and
N. Chand.
Histamine receptor mechanism of the lung.
In: Pharmacology of Histamine Receptors, edited by C. R. Ganellin,
and M. E. Parsons. Bristol, UK: Wright, 1982, p. 298-322.
27.
Felder, C. C.,
R. Y. Kanterman,
A. L. Ma,
and
J. Axelrod.
A transfected m1 muscarinic acetylcholine receptor stimulates adenylate cyclase via phosphatidylinositol hydrolysis.
J. Biol. Chem.
264:
20356-20362,
1989
28.
Fraser, C. M.,
C.-D. Wang,
D. A. Robinson,
J. D. Gocayne,
and
J. C. Venter.
Site-directed mutagenesis of m1 muscarinic acetylcholine receptors: conserved aspartic acids play important roles in receptor function.
Mol. Pharmacol.
36:
840-847,
1989[Abstract].
29.
Frieling, T.,
H. J. Cooke,
and
J. D. Wood.
Synaptic transmission in submucosal ganglia of guinea pig distal colon.
Am. J. Physiol.
260 (Gastrointest. Liver Physiol. 23):
G842-G849,
1991
30.
Frieling, T.,
J. D. Wood,
and
H. J. Cooke.
Submucosal reflexes: distension-evoked ion transport in the guinea pig distal colon.
Am. J. Physiol.
263 (Gastrointest. Liver Physiol. 26):
G91-G96,
1992
31.
Frieling, T.,
H. J. Cooke,
and
J. D. Wood.
Histamine receptors on submucous neurons in guinea pig colon.
Am. J. Physiol.
264 (Gastrointest. Liver Physiol. 27):
G74-G80,
1993
32.
Fukushima, Y.,
T. Asano,
H. Katagiri,
M. Aihara,
T. Saitoh,
M. Anai,
M. Funaki,
T. Ogihara,
K. Inukai,
N. Matsuhashi,
Y. Oka,
Y. Yazaki,
and
K. Sugano.
Interaction between the two signal transduction systems of the histamine H2 receptor: desensitizing and sensitizing effects of histamine stimulation on histamine-dependent cAMP production in Chinese hamster ovary cells.
Biochem. J.
320:
27-32,
1996[Medline].
33.
Gantz, I.,
M. Schaffer,
J. Del Valle,
C. Logsdon,
V. Campbell,
M. Uhler,
and
T. Yamada.
Molecular cloning of a novel gene encoding the histamine H2 receptor.
Proc. Natl. Acad. Sci. USA
88:
429-433,
1991[Abstract].
34.
Gantz, I.,
G. Munzert,
T. Tashiro,
M. Schaffer,
L. Wang,
J. Del Valle,
and
T. Yamada.
Molecular cloning of the human histamine H2 receptor.
Biochem. Biophys. Res. Commun.
178:
1386-1392,
1991[Medline].
35.
Gantz, I.,
J. Del Valle,
L. Wang,
T. Tashiro,
G. Munzert,
Y.-J. Guo,
Y. Konda,
and
T. Yamada.
Molecular basis for the interaction of histamine with the histamine H2 receptor.
J. Biol. Chem.
267:
20840-20843,
1992
36.
Grund, V. R.,
N. D. Goldberg,
and
D. B. Hunninghake.
Histamine receptors in adipose tissue: involvement of cyclic adenosine monophosphate and the H2-receptor in the lipolytic response to histamine in isolated canine fat cells.
J. Pharmacol. Exp. Ther.
195:
176-184,
1975[Abstract].
37.
Gudermann, T.,
M. Birnbaumer,
and
L. Birnbaumer.
Evidence for dual coupling of the murine luteinizing hormone receptor to adenylyl cyclase and phosphoinositide breakdown and Ca2+ mobilization.
J. Biol. Chem.
267:
4479-4488,
1992
38.
Haas, H. L.,
and
R. W. Greene.
Effect of histamine on hippocampal pyramidal cells of the rat in vitro.
Exp. Brain Res.
62:
123-130,
1986[Medline].
39.
Hakanson, R.,
C. Wahlestedt,
L. Wetlin,
S. Vallgren,
and
F. Sundler.
Neuronal histamine in the gut wall releasable by gastrin and cholecystokinin.
Neurosci. Lett.
42:
305-310,
1983[Medline].
40.
Hausdorff, W. P.,
M. G. Caron,
and
R. J. Lefkowitz.
Turning off the signal: desensitization of the -adrenergic receptor function.
FASEB J.
4:
2881-2889,
1990[Abstract].
41.
Hill, S. J.
Distribution, properties, and functional characteristics of three classes of histamine receptors (Abstract).
Pharmacol. Rev.
42:
45,
1990[Abstract].
42.
Hogan, D. L.,
B. Yao,
K. E. Barrett,
and
J. I. Isenberg.
Histamine inhibits prostaglandin E2-stimulated rabbit duodenal bicarbonate secretion via H2 receptors and enteric nerves.
Gastroenterology
108:
1676-1682,
1995[Medline].
43.
Johnson, C. L.,
H. Weinstein,
and
J. P. Green.
Studies on the H2-receptors coupled to cardiac adenylate cyclase: effects of guanyl nucleotides and structural requirements for agonist activity.
Biochem. Biophys. Res. Commun.
587:
155-168,
1979.
44.
Johnson, C. L.,
and
D. G. Sawutz.
Desensitization of histamine H2 receptors in human leukemia cells.
In: Frontiers in Histamine Research, edited by C. R. Ganellin,
and J. C. Schwartz. Oxford, UK: Pergamon, 1985, p. 79-88.
45.
Kahlson, G.,
and
E. Rosengren.
New approaches to the physiology of histamine.
Physiol. Rev.
48:
155-196,
1968
46.
Kanof, P. D.,
L. R. Hegstrand,
and
P. Greengard.
Biochemical properties of histamine-sensitive adenylate cyclase from guinea-pig cardiac ventricular muscle.
Arch. Biochem. Biophys.
182:
321-334,
1977[Medline].
47.
Kent, L.,
and
H. T. Debas.
Peripheral regulation of gastric acid secretion.
In: Physiology of the Gastrointestinal Tract (3rd ed.), edited by L. R. Johnson. New York: Raven, 1994, p. 1185-1226.
48.
Kobilka, B. K.,
T. Freille,
H. G. Dohlman,
M. A. Bolanowski,
R. A. F. Dixon,
P. Keller,
M. G. Caron,
and
R. J. Lefkowitz.
Delineation of the intronless nature of the genes for the human and hamster 2-adrenergic receptor and their putative promoter regions.
J. Biol. Chem.
262:
7321-7327,
1987
49.
Kühn, B.,
A. Schmid,
C. Harteneck,
T. Gudermann,
and
G. Schultz.
G proteins of the Gq family couple the H2 histamine receptor to phospholipase C.
Mol. Endocrinol.
10:
1687-1707,
1996.
50.
Lefkowitz, R. J.
G protein coupled receptor kinases.
Cell
74:
409-412,
1993[Medline].
51.
Leurs, R.,
M. J. Smith,
and
H. Timmerman.
Molecular pharmacological aspects of histamine receptors.
Pharmacol. Ther.
66:
413-463,
1995[Medline].
52.
Leurs, R.,
M. J. Smit,
C. P. Tensen,
A. M. Ter Laak,
and
H. Timmerman.
Site-directed mutagenesis of the histamine H1-receptor reveals a selective interaction of asparagine 207 with subclasses of H1-receptor agonists.
Biochem. Biophys. Res. Commun.
201:
295-301,
1994[Medline].
53.
Lewin, M. J., A. Bado, Y. Cheriti, and F. Reyl-Desmars.
The gastric H3 receptor: a
review. Yale J. Biol. Med. 65, Suppl. 6: 607-611, 1992.
54.
Libert, F.,
M. Parmentier,
A. Lefort,
C. Dinsart,
J. Van Sande,
C. Maenhaut,
M.-J. Simons,
J. E. Dumont,
and
G. Vassart.
Selective amplification and cloning of four new members of the G protein-coupled receptor family.
Science
244:
569-572,
1989[Medline].
55.
Lungstrom, M.,
and
C. S. Chew.
Calcium oscillations and morphological transformations in single cultured gastric parietal cells.
Am. J. Physiol.
260 (Gastrointest. Liver Physiol. 23):
G67-G78,
1991.
56.
Lichtenstein, L. M.,
and
E. Gillespie.
The effect of the H1- and H2 antihistamines on "allergic" histamine release and its inhibition by histamine.
J. Pharmacol. Exp. Ther.
192:
441-450,
1975[Abstract].
57.
MacNulty, E. E.,
S. J. McClue,
I. L. Carr,
T. Jess,
M. J. O. Wakelam,
and
G. Milligan.
2-C10 adrenergic receptors expressed in rat 1 fibroblasts can regulate both adenylcyclase and phospholipase D-mediated hydrolysis of phosphatidylcholine by interacting with pertussis toxin-sensitive guanine nucleotide-binding proteins.
J. Biol. Chem.
267:
2149-2156,
1992
58.
Mezey, E.,
and
M. Palkovits.
Localization of targets for anti-ulcer drugs in cells of the immune system.
Science
258:
1662-1665,
1992[Medline].
59.
Milligan, G.
Mechanisms of multifunctional signalling by G protein-linked receptors.
Trends Pharmacol. Sci.
14:
239-244,
1993[Medline].
60.
Milligan, G.,
R. A. Bond,
and
M. Lee.
Inverse agonism: pharmacological curiosity or potential therapeutic strategy?
Trends Pharmacol. Sci.
16:
10-13,
1995[Medline].
61.
Mitsuhashi, M.,
T. Mitsuhashi,
and
D. G. Payan.
Multiple signaling pathways of histamine H2 receptors.
J. Biol. Chem.
264:
18356-18362,
1989
62.
Morini, G., J. F. Kuemmerle, M. Impicciatore, J. R. Grider, and G. M. Makhlouf. Coexistence of
histamine H1 and
H2 receptors coupled to distinct
signal transduction pathways in isolated intestinal muscle cells.
J. Pharmacol. Exp. Ther. 264, Suppl. 2: 1993, p. 598.
63.
Nishi, T.,
T. Koike,
T. Oka,
M. Maeda,
and
M. Futai.
Identification of the promoter region of the human histamine H2 receptor gene.
Biochem. Biophys. Res. Commun.
210:
616-623,
1995[Medline].
64.
Nishizuka, Y.
Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C.
Science
258:
607-608,
1992[Medline].
65.
Ohta, K.,
H. Hayashi,
H. Mizuguchi,
H. Kagamiyama,
K. Fujimoto,
and
H. Fukui.
Site-directed mutagenesis of the histamine H1 receptor: roles of aspartic acid 107, asparagine 198, and threonine 194.
Biochem. Biophys. Res. Commun.
203:
1096-1101,
1994[Medline].
66.
Okamota, T.,
Y. Murayama,
Y. Hayashi,
M. Inagaki,
E. Ogata,
and
I. Nishimoto.
Identification of a Gs activator region of the 2-adrenergic receptor that is autoregulated via protein kinase A-dependent phosphorylation.
Cell
67:
723-730,
1991[Medline].
67.
Orange, P. R.,
P. R. Heath,
S. R. Wright,
and
R. C. A. Pearson.
Allelic variations of the human histamine H2 receptor gene.
Neuroreport
7:
1293-1296,
1996[Medline].
68.
Ottoson, A.,
I. Jansen,
and
L. Edvinsson.
Characterization of histamine receptors in isolated human cerebral arteries.
Br. J. Pharmacol.
94:
901-907,
1988[Abstract].
69.
Panula, P.
Histamine in the nervous system.
In: Neurohistochemistry: Modern Methods and Applications, edited by P. Panula,
H. Paivarinta,
and S. Soinila. New York: Alan R. Liss, 1992, p. 425-442.
70.
Rangachari, P. K.
Histamine: mercurial messenger in the gut.
Am. J. Physiol.
262 (Gastrointest. Liver Physiol. 25):
G1-G13,
1992
71.
Raymond, J. R.
Multiple mechanisms of receptor-G protein signaling specificity.
Am. J. Physiol.
269 (Renal Fluid Electrolyte Physiol. 38):
F141-F158,
1995
72.
Reyl-Desmars, F.,
Y. Cherifi,
M. Le Romancer,
C. Pigeon,
S. Le Roux,
and
M. J. M. Lewin.
Solubilization and purification of the H2-histamine receptor from the human tumoral gastric cells HGT-1.
C. R. Acad. Sci. Paris
312:
221-224,
1991[Medline].
73.
Ruat, M.,
E. Taiffort,
J.-M. Arrang,
R. Leurs,
and
J. C. Schwartz.
Cloning and tissue expression of a rat histamine H2 receptor gene.
Biochem. Biophys. Res. Commun.
179:
1470-1478,
1991[Medline].
74.
Sansoni, P.,
E. D. Silverman,
M. M. Khan,
K. L. Melmon,
and
E. G. Engleman.
Immunoloregulatory T cells in man: histamine-induced suppressor T cells are derived from Leu2+ (T+) subpopulation distinct from that which gives rise to cytotoxic T cells.
J. Clin. Invest.
75:
650-656,
1985[Medline].
75.
Schwartz, J. C.,
J. M. Arrang,
M. Garbarg,
and
H. Pollard.
Histamine H3 receptors in the brain: potent and selective ligands.
Psychopharmacol. Ser.
7:
10-19,
1989[Medline].
76.
Seifert, R.,
A. Höer,
I. Schwaner,
and
A. Buschauer.
Histamine increases cytosolic Ca2+ in HL-60 promyelocytes predominantly via H2 receptors with a unique agonist/antagonist profile and induces functional differentiation.
Mol. Pharmacol.
42:
235-241,
1992[Abstract].
77.
Seuwem, K.,
and
J. Pouyssegur.
G-protein-controlled signal transduction pathways and the regulation of cell proliferation.
Adv. Cancer Res.
58:
75-94,
1992[Medline].
78.
Smit, M. J.,
H. Timmerman,
A. E. Alewijnse,
M. Punin,
I. Van den Nieuwenhof,
J. Blauw,
J. Van Minnen,
and
R. Leurs.
Visualization of agonist-induced internalization of histamine H2 receptors.
Biochem. Biophys. Res. Commun.
214:
1138-1145,
1995[Medline].
79.
Smit, M. J.,
R. Leurs,
A. E. Alewijnse,
J. Blauw,
G. P. Van Nieuw Amerongen,
Y. Van de Vrede,
E. Roovers,
and
H. Timmerman.
Inverse agonism of histamine H2 antagonists accounts for upregulation of spontaneously active histamine H2 receptors.
Proc. Natl. Acad. Sci. USA
93:
6802-6807,
1996
80.
Smit, M. J.,
H. Timmerman,
J. Blauw,
M. W. Beukers,
E. Roovers,
E. H. Jacobs,
M. Hoffmann,
and
R. Leurs.
The C terminal tail of the histamine H2 receptor contains positive and negative signals important for signal transduction and receptor downregulation.
J. Neurochem.
67:
1791-1800,
1996[Medline].
81.
Smith, T.,
J. W. Clark,
and
M. B. Popp.
Regression of melanoma nodules in a patient treated with ranitidine.
Arch. Intern. Med.
147:
1815-1816,
1987[Abstract].
82.
Soll, A. H.,
and
A. Wollin.
Histamine and cyclic AMP in isolated canine parietal cells.
Am. J. Physiol.
237 (Endocrinol. Metab. Gastrointest. Physiol. 6):
E444-E450,
1979[Medline].
83.
Soll, A. H.,
and
T. Berglindh.
Receptors that regulate gastric secretory function.
In: Physiology of the Gastrointestinal Tract (3rd ed.). New York: Raven, 1994, p. 1139-1170.
84.
Strader, C. D.,
R. A. F. Dixon,
A. H. Cheung,
M. R. Candelore,
A. D. Blaker,
and
I. S. Sigal.
Mutations that uncouple the -adrenergic receptor from Gs and increase agonist affinity.
J. Biol. Chem.
262:
16439-16443,
1987
85.
Strader, C. D.,
I. S. Sigal,
M. R. Candelore,
E. Rands,
W. S. Hill,
and
R. A. F. Dixon.
Conserved aspartic acid residues 79 and 113 of the -adrenergic receptor have different roles in receptor function.
J. Biol. Chem.
263:
10267-10271,
1988
86.
Strader, C. D.,
M. R. Candelore,
W. S. Hill,
I. S. Sigal,
and
R. A. F. Dixon.
Identification of two serine residues involved in agonist activation of the -adrenergic receptor.
J. Biol. Chem.
264:
13572-13578,
1989
87.
Strader, C. D.,
I. S. Sigal,
and
R. A. F. Dixon.
Structural basis of -adrenergic receptor function.
FASEB J.
3:
1825-1832,
1989
88.
Tari, A.,
G. Yamamoto,
K. Sumii,
M. Sumii,
Y. Takehara,
K. Haruma,
G. Kajiyama,
V. Wu,
G. Sachs,
and
J. H. Walsh.
Roles of histamine2 receptor in increased expression of rat gastric H+-K+-ATPAse -subunit induced by omeprazole.
Am. J. Physiol.
265 (Gastrointest. Liver Physiol. 28):
G752-G758,
1993
89.
Tolone, G.,
L. Bonsera,
and
G. M. Potieri.
Histamine binding to H2-receptors stimulates phospholipid methylation in mast cells.
Experientia
38:
966-968,
1982[Medline].
90.
Tonnesen, H.,
S. Bulow,
K. Fischerman,
A. Hjortrup,
V. M. Pedersen,
L. B. Svendsen,
U. Knigge,
P. Damm,
P. Hesselfeld,
I. K. Pedersen,
O. J Siemssen,
and
P. M. Christiansen.
Effect of cimetidine on survival after gastric cancer.
Lancet
2:
990-992,
1988[Medline].
91.
Tota, M. R.,
and
C. D. Strader.
Characterization of the binding domain of the -adrenergic receptor with the fluorescent antagonist carazolol. Evidence for a buried ligand binding site.
J. Biol. Chem.
265:
16891-16897,
1990
92.
Traiffort, E.,
H. Pollard,
J. Moreau,
M. Ruat,
J. C. Schwartz,
M. I. Martinez-Mir,
and
J. M. Palacios.
Pharmacological characterization and autoradiographic localization of histamine H2 receptors in human brain identified with [125I]iodoaminopotentidine.
J. Neurochem.
59:
290-299,
1992[Medline].
93.
Traiffort, E.,
M. Ruat,
J.-M. Arrang,
R. Leurs,
D. Piomelli,
and
J. C. Schwartz.
Expression of a cloned rat histamine H2 receptor mediating inhibition of arachidonate release and activation of cAMP accumulation.
Proc. Natl. Acad. Sci. USA
89:
2649-2653,
1992[Abstract].
94.
Traiffort, E.,
M. L. Vizuete,
J. Tardivel-Lacombe,
E. Souil,
J.-C. Schwartz,
and
M. Ruat.
The guinea pig histamine H2 receptor: gene cloning, tissue expression and chromosomal localization of its human counterpart.
Biochem. Biophys. Res. Commun.
211:
570-577,
1995[Medline].
95.
Ucar, K.
The effects of histamine H2 receptor antagonists on melanogenesis and cellular proliferation in melanoma cells in culture.
Biochem. Biophys. Res. Commun.
177:
545-550,
1991[Medline].
96.
Vallar, L.,
C. Muca,
M. Magni,
P. Albert,
J. Bunzow,
J. Meldolesi,
and
O. Civelli.
Differential coupling of dopaminergic D2 receptors expressed in different cell types.
J. Biol. Chem.
265:
10320-10326,
1990
97.
Van Sande, J.,
E. Raspé,
J. Perret,
C. Lejeune,
C. Maenhaut,
G. Vassart,
and
J. E. Dumont.
Thyrotropin activates both the cyclic AMP and the PIP2 cascades in CHO cells expressing the human cDNA of TSH receptor.
Mol. Cell. Endocrinol.
74:
R1-R6,
1990[Medline].
98.
Wang, L.,
R. Hunter,
I. Gantz,
M. Hoeltzel,
and
J. Del Valle.
Characterization of the structural components of the H2 histamine receptor involved in activation of adenylate cyclase and phospholipase C (Abstract).
Gastroenterology
108:
A1014,
1995.
99.
Wang, L.,
I. Gantz,
and
J. Del Valle.
Histamine H2 receptor activates adenylate cyclase and PLC via separate GTP-dependent pathways.
Am. J. Physiol.
271 (Gastrointest. Liver Physiol. 34):
G613-G620,
1996
100.
Wang, L.,
M. Hoeltzel,
K. Butler,
A. Todisco,
and
J. Del Valle.
Activation of the human histamine H2 receptor induces c-fos gene transcription (Abstract).
Gastroenterology
110:
A1131,
1996.
101.
Wang, L.,
I. Gantz,
K. Butler,
M. Hoeltzel,
and
J. Del Valle.
Characterization of H2 receptor structural requirements for dual signaling: application of 2/H2 chimeric receptors (Abstract).
Gastroenterology
112:
A1198,
1997.
102.
Wang, L.,
M. Wang,
A. Todisco,
T. Suzuki,
and
J. Del Valle.
Histamine H2 receptor mediated regulation of c-fos involves both PKC and PKA signaling pathways (Abstract).
Gastroenterology
112:
A1199,
1997.
103.
Watson, S. A.,
L. J. Wilkinson,
J. F. R. Robertson,
and
J. D. Hardcastle.
Effect of histamine on the growth of human gastrointestinal tumours: reversal by cimetidine.
Gut
34:
1091-1096,
1993[Abstract].
104.
Warbanow, W., and A. Wollenberger. Mechanical responses of
cultured pre- and neonatal myocytes. J. Mol. Cell.
Cardiol. 11, Suppl. 1:
64, 1979.
105.
Weinstein, H.,
D. Chou,
C. L. Johnson,
S. Kang,
and
J. P. Green.
Tautomerism and the receptor action of histamine: a mechanistic model.
Mol. Pharmacol.
12:
738-745,
1976[Abstract].
106.
Whitehead, R. J.,
D. J. Taylor,
J. M. Evanson,
I. R. Hasrt,
and
D. E. Woolley.
Demonstration of histamine H2 receptors on human melanoma cells.
Biochem. Biophys. Res. Commun.
151:
518-523,
1988[Medline].
107.
Woolley, D. E.,
D. Eckley,
L. C. Tetlow,
and
R. J. Whitehead.
Effect of mast cell products and histamine on the proliferative behaviour of human melanoma and carcinoma cells in vitro.
Agents Actions
38:
C175-C177,
1993.