THEMES
G Protein-Coupled Receptors in Gastrointestinal Physiology
I. CCK receptors: an exemplary family*

Stephen A. Wank

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1804

    ABSTRACT
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Abstract
Introduction
Conclusions
References

The CCK and gastrin families of peptides act as hormones and neuropeptides on central and peripheral receptors to mediate secretion and motility in the gastrointestinal tract in the physiological response to a normal meal. Thus far, two CCK receptors have been molecularly identified to mediate the actions of CCK and gastrin, CCK-A and CCK-B receptors (CCK-AR and CCK-BR, respectively). The regulation of CCK-AR and CCK-BR affinity by guanine nucleotides and the receptor activation of G protein-dependent stimulation of phospholipase C and adenylyl cyclase suggested that they were guanine nucleotide-binding protein-coupled receptors [G protein-coupled receptors (GPCRs)]; however, the eventual cloning of their cDNAs revealed their heptahelical structure and confirmed their membership in the GPCR superfamily. The gastrointestinal system is a rich source of neuroendocrine hormones that interact with a large number of GPCRs to regulate the complex tasks of digestion, absorption, and excretion of a meal. This article focuses on the CCK family of GPCRs, and its activities in the gastrointestinal system.

cholecystokinin; gastrin; expression; cDNA; signal transduction

    INTRODUCTION
Top
Abstract
Introduction
Conclusions
References

THE PHYSIOLOGICAL REGULATION of complex organisms requires the interaction of extracellular regulators with cell surface and intracellular receptors of the target cell. This review addresses the largest class of receptors, the structurally related superfamily of guanine nucleotide-binding protein-coupled receptors [G protein-coupled receptors (GPCRs)]. It is estimated that 1-2% of mammalian genes encode 1,000 or more different proteins belonging to this superfamily of receptors. GPCRs share the signature seven-transmembrane-spanning, alpha -helical domain motif and the ability to transduce responses to a number of diverse extracellular stimuli, including photons, odorants, hormones, neurotransmitters, ions, and proteases, by activating heterotrimeric G proteins that subsequently regulate intracellular effectors. The gastrointestinal system is a rich source of neuroendocrine hormones that interact with at least 10 families of GPCRs containing more than 30 known receptor subtypes to regulate the complex tasks of digestion, absorption, and excretion of a meal. This article focuses on a single family, the CCK family of receptors. Although CCK receptors are widely distributed outside the gastrointestinal system, especially in the nervous system, this review is limited predominantly to the gastrointestinal system.

    THE NATIVE LIGANDS: CCK AND GASTRIN

CCK-like peptides are ancient brain-gut peptides conserved over a long period of evolution, having been shown to be present in neurons and gut endocrine cells as far back as protochordates. In humans, CCK occurs as COOH-terminal amidated 58- and 8-amino acid major forms processed from a 115-amino acid preprohormone and is expressed in neurons throughout the central and peripheral autonomic nervous systems and in intestinal endocrine cells and neurons, where it is released in response to a meal. Full biological activity resides in the COOH-terminal seven amino acids, although full potency requires the octapeptide sulfated at the tyrosine in the seventh position from the COOH terminus. alpha -Amidation of the COOH terminus is essential for biological activity. Gastrin also occurs in multiple molecular forms processed from a 101-amino acid preprohormone, with the COOH-terminal amidated 34- and 17-amino acid processed forms predominating in the duodenum and gastric antrum, respectively, where they are released in response to a meal. Full biological activity resides in the COOH-terminal tetrapeptide, although with much lower potency, and as with CCK, alpha -amidation is essential for biological activity (Fig. 1) (27).


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Fig. 1.   Structure of CCK, gastrin, and subtype-selective nonpeptide agonists and antagonists. A: primary sequence of the most predominant mammalian forms of CCK: CCK-58, CCK-33, and CCK-8. B: major sulfated form of gastrin (~50% sulfated), gastrin-17-II (<E, denotes a pyroglutamic acid). C-F: planar representations of structures of substituted benzodiazepine CCK receptor antagonists (C-E) L-364,718 [CCK-A receptor (CCK-AR) preferring], L-365,260 [CCK-B receptor (CCK-BR) preferring], and L-740,093 (second generation, CCK-BR preferring) and CCK-AR agonist GW-5823 (F).

    CCK RECEPTOR CLASSIFICATION

Receptors for CCK were first characterized on pancreatic acinar cells and identified as CCK type A receptors (CCK-AR), with the subsequent discovery in the same year of a second receptor with a different pharmacology in the brain, CCK type B receptors (CCK-BR). These two types of CCK receptor could be pharmacologically distinguished on the basis of their affinity for the agonists CCK and gastrin, which share the same COOH-terminal pentapeptide amide sequence but differ in sulfation at the sixth (gastrin) and seventh (CCK) tyrosyl residues, and by recently developed subtype-specific antagonists. CCK-AR are highly selective (500- to 1,000-fold) for sulfated analogs of CCK, whereas CCK-BR have similarly high affinity for both sulfated and nonsulfated peptide analogs of CCK and gastrin peptides. Formerly, the gastrin receptor mediating acid secretion in the stomach was thought to constitute a third type of high-affinity receptor on the basis of its location, small differences in affinity for CCK and gastrin-like peptides, and the reversal in relative affinityfor receptor subtype-selective antagonists in canine gastric glands. Subsequent cloning of gastrin receptors from canine stomach and CCK-BR from canine brain revealed their molecular identity, leading to the classification of gastrin receptors as CCK-BR (27).

    LOCATION AND FUNCTION OF CCK RECEPTORS

Gastrin and CCK are released from gastrointestinal endocrine cells lining the mucosa of the stomach (antral G cells) and upper small bowel (I cells), respectively, in response to protein and lipid in a meal and bind CCK-AR and CCK-BR present on a variety of gastrointestinal target tissues to regulate digestion and absorption (Table 1). Gastrin regulates the release of acid by directly activating CCK-BR on parietal cells and, more importantly, CCK-BR on nearby enterochromaffin-like (ECL) cells that release histamine to stimulate acid via H2 histamine receptors on parietal cells. Both CCK-AR and CCK-BR are present on gastric somatostatin-releasing D cells, where CCK affects the CCK-AR to stimulate the inhibition of acid secretion through the release of somatostatin and subsequent inhibition of both gastrin and histamine via somatostatin type 2 receptors on G and ECL cells. CCK-AR regulate the release of pepsinogen from gastric chief cells. CCK-AR on smooth muscle cells and neural intermediates cause relaxation of the lower esophageal sphincter, increased pyloric sphincter tone, and relaxation of the gastric corpus, resulting in delayed gastric emptying, gallbladder contraction, relaxation of the sphincter of Oddi, decreased small bowel transit time, and increased colonic transit time. CCK-AR on duodenal vagal afferent neurons and to a lesser degree on pancreatic acinar cells regulate enzyme secretion in animals, whereas CCK-BR, presumably on vagal afferent neurons and intrapancreatic cholinergic neurons, regulate secretion in humans. Gastrin and CCK have trophic effects on parietal and ECL cells in the gastric mucosa and on pancreatic acini, respectively, as well as on a number of gastrointestinal and nongastrointestinal tumoral cell lines (27).

                              
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Table 1.   Characteristics of the two major subtypes of CCK receptors

                              
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Table 2.   Location and function of CCK receptor subtypes

    GASTROINTESTINAL REGULATION OF RENAL FUNCTION

After the cloning of the human CCK-BR, a search for previously unappreciated tissue expression of the CCK-BR by Northern blot hybridization revealed relatively high expression in the kidney. Although it had been hypothesized for many years that gastrointestinal hormones such as gastrin that become elevated in response to a meal play a significant role in the acute regulation of the renal handling of absorbed nutrients, the actual hormones involved as well as their site and mechanism of action have remained elusive. Pisegna et al. (17) describe the distribution of CCK-BR to proximal tubules in the kidney by immunohistochemistry and RT-PCR in a pattern consistent with this integrative function. Elevation of serum gastrin in rats either by stimulation of a gavaged meal or infusion of physiological doses resulted in a fourfold increase in urinary Na+ excretion and fractional Na+ excretion and an eightfold increase in urine output that could be inhibited by the CCK-BR-specific antagonist L-365,260. The studies of Pisegna et al. (17) provide, for the first time, direct evidence for gastrointestinal hormones as mediators of the gastrointestinal-renal axis and have profound implications in understanding the influence of feeding on renal function.

    CCK RECEPTOR COUPLING TO G PROTEINS

The regulation of CCK-AR and CCK-BR affinity by guanine nucleotides and the receptor activation of G protein-dependent stimulation of phospholipase C (PLC) and adenylyl cyclase suggested that they were GPCRs. Cloning of the CCK-AR from pancreas (28) and the CCK-BR from stomach and brain (8, 29) revealed their heptahelical structure (Fig. 2) and confirmed their membership in the GPCR superfamily. The insensitivity of CCK-AR and CCK-BR inositol phosphate signaling to pertussis toxin suggested coupling through the Gq family of G proteins. More recently, a study using both PLC and G protein alpha -subunit-specific antibodies in pancreatic cell membranes has indicated that both Gq and G11alpha are present in pancreas and that the CCK-AR couples to Gq/11 to activate PLC-beta 1, as measured by CCK-8-stimulated increase in phosphatidylinositol 4,5-bisphosphate-specific PLC activity (16). Another study of CCK-AR in acutely dispersed substantia nigra dopaminergic neurons confirmed the presence of Gq/11 by RT-PCR and used Gq/11-specific antibodies to inhibit CCK-8-evoked cationic currents of whole cell patch-clamp recordings (31). The region of the CCK-BR interacting with Gq was determined in mutated CCK-BR transiently expressed into COS-7 cells and Xenopus oocytes. K333M, K334T, and R335L (Fig. 2) mutations resulted in the loss of Gq activation without affecting receptor affinity (25). The COOH-terminal portion of the third cytoplasmic loop (Ci3) of most GPCRs contains a stretch of charged residues (including CCK-AR and CCK-BR) that are thought to form an amphipathic alpha -helical extension of the sixth transmembrane domain (TM VI) in a critical orientation for G protein activation (30); thus these results suggest that the CCK-BR Ci3 is also likely to form an alpha -helical extension of TM VI necessary for the specific activation of Gq. Similar to several other GPCRs, CCK-AR is capable of coupling to both PLC and adenylyl cyclase at physiological concentrations in native cells (10). It is not clear whether this is a result of dual coupling to Gs and Gq or simply the result of G protein beta gamma -subunit activation of adenylyl cyclase. However, a recent CCK receptor chimeric study bearing on this issue exchanged the first intracellular loop between the CCK-AR and CCK-BR and found that Arg68 and Asn69 in the first intracellular loop of the CCK-AR were important for activation of adenylyl cyclase without affecting Gq coupling. These results support the direct coupling of the CCK-AR to both Gs and Gq (32).


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Fig. 2.   Schematic models of rat CCK-AR (A) and CCK-BR (B). Deduced primary amino acid sequences of rat CCK-AR and CCK-BR showing putative transmembrane helices, NH2-linked glycosylation sites (tridents), protein kinase C and protein kinase A (-PO3) phosphorylation sites, potential disulfide bridge (-S-S-) between conserved cysteines in the first and second extracellular loops, and a potential palmitoylated (jagged line) conserved cysteine in the cytoplasmic tail (-NH2, amino terminus; -COOH, carboxy terminus). bullet , Conserved (identical) residues between CCK-AR and CCK-BR (27).

    A NEW POTENT AND SELECTIVE CCK-BR ANTAGONIST

The development of radioimmunoassays, radioligands with full efficacy and potency, immunocytochemistry, and more recently receptor subtype-specific agonists and antagonists has greatly accelerated discoveries in gastrointestinal endocrinology. It is clear from the distribution of CCK receptors described above that many tissues and even single cells express both CCK-AR and CCK-BR and that gastrin is the only native selective agonist. Therefore, the recently available selective CCK-AR agonist, A-71378, and CCK-AR and CCK-BR subtype-selective substituted 1,4-benzodiazepine antagonists such as L-364,718 and L-365,260, respectively (Fig. 1), have been extremely useful in sorting out the location and physiological functions attributed to each receptor subtype (4). The usefulness of L-365,260 has been limited by its relatively low selectivity for CCK-BR vs. CCK-AR (80- to 280-fold depending on the species, and even a reversal of affinity in canines) and its partial agonist activity. Recently, a second generation benzodiazepine antagonist, L-740,093 (Fig. 1), has been developed with higher affinity (IC50 = 0.1 nM for acid secretion), higher selectivity (16,000-fold) for CCK-BR, and improved aqueous solubility (15).

    CCK-AR AND SATIETY

CCK acting at the CCK-AR on capsaicin-sensitive vagal afferent neurons has been shown to reduce food intake in animals and humans (4). An exciting recent study demonstrated that a subthreshold intraperitoneal dose of CCK-8 acting at vagal afferent CCK-AR synergized with low doses of leptin to cause an accelerated dose-dependent decrease in food intake in lean mice (2). Although the peptide A-71378 [desamino-Tyr(SO4)-Nle-Gly-Trp-Nle-(N-methyl)Asp-Phe-NH2] is a high-affinity, selective agonist at the CCK-AR, an orally active (nonpeptide) CCK-AR-selective agonist would be more useful in the treatment of human obesity. Evaluation of a series of 3-(1H-indazol-3-yl-methyl)-1,5-benzodiazepines, using an in vivo mouse gallbladder emptying assay, identified a CCK-AR agonist, GW-5823 (Fig. 1), with relatively high potency (EC50 = 70 nM), full efficacy, and a modest 50-fold selectivity for CCK-AR vs. CCK-BR. Although these compounds have poor oral bioavailability and high clearance, in part due to delayed gastric emptying and rapid liver metabolism, they were still potent and efficacious as oral anorectic agents in a rat conditioned feeding model (5). With further improvement these 1,5-substituted benzodiazepine analogs may become the first orally effective CCK-AR-mediated satiety agents for the treatment of human obesity.

    DISEASE-CAUSING MUTATIONS IN GPCR

Advances in molecular biology have led to an increased understanding of inherited and spontaneously mutated gene-based diseases. Cloning of mutant GPCRs, for example, has revealed the molecular basis of human diseases due to decreased receptor function, such as color blindness and retinitis pigmentosa (cone opsins and rhodopsin mutants), hormone-resistant X-linked nephrogenic diabetes insipidus (V2 vasopressin receptor), familial hypocalciuric hypercalcemia (Ca2+-sensing receptor), hereditary isolated glucocorticoid deficiency (ACTH receptor), partial thyrotropin resistance syndrome [thyrotropin-stimulating hormone receptor (TSHR)], and familial Leydig cell hyperplasia (luteinizing hormone receptor). Activating mutations of GPCRs can also cause diseases such as retinitis pigmentosa and congenital night blindness (rhodopsin), familial male precocious puberty (luteinizing hormone receptor), hyperfunctional thyroid adenomas, hyperfunctional thyroid hyperplasia (TSHR), and autosomal dominant hypocalcemia (Ca2+-sensing receptor) (22). It was hoped that cloning of gastrointestinal hormone receptors, especially the widely distributed CCK receptors, would lead to establishing the molecular basis for diseases affecting many of the gastrointestinal organs. However, GPCR mutation-based diseases tend to be quite rare. An interesting case has been reported of a woman with gallstones and obesity ascribed to abnormal processing of transcripts from a normal CCK-AR gene, resulting in the predominance of mRNA with a 262-bp deletion corresponding to the third exon. Unfortunately, other affected family members were not examined, and expected splicing abnormalities in messages for other genes were not studied, so that an association could only be established between the common phenotype of gallstones and obesity and the putative RNA processing abnormality in the affected patient (11).

The rodent Mastomys natalensis, with a genetic predisposition toward development of gastric carcinoids of ECL origin, has served as a model for studying the neoplastic potential of hypergastrinemia acting at the ECL CCK-BR. Hypergastrinemia acclerates the development of Mastomys gastric carcinoids in which the ECL cells have increased CCK-BR expression compared with native ECL cells. This association has prompted further investigation into the possible growth-promoting role of CCK-BR in the transformation of ECL cells (12). Schaffer et al. (21) recently demonstrated a higher basal level of agonist-independent signaling of Mastomys CCK-BR in transfected COS cells compared with human CCK-BR, due to a four-amino acid species polymorphism in the sixth transmembrane domain, suggesting a possible contributing mechanism underlying the propensity of Mastomys to develop gastric carcinoids. Whether these results are applicable to human disease is uncertain; however, hypergastrinemia, due either to achlorhydria or sporadic Zollinger-Ellison syndrome, rarely results in ECL carcinoids.

    TARGETED DISRUPTION OF THE CCK-BR GENE IN TRANSGENIC MICE

The development of transgenic animals has already provided insight into tissue and temporal expression of hormones such as gastrin (26). More recently, transgenic animals with targeted disruption of individual genes for gastrointestinal hormones and their GPCRs have been created with the hope of revealing previously unknown sites of expression and physiological function as well as confirming our present knowledge. Targeted disruption of the CCK-BR caused selective decreased growth of gastric parietal and ECL cells, confirming the growth-promoting effects of gastrin at the CCK-BR seen in patients with hypergastrinemia due to Zollinger-Ellison syndrome. Also, as expected, these mice were hypochlorhydric and hypergastrinemic (13). Perhaps more interesting and somewhat disappointing was the absence of other abnormalities, given the wide expression and wide range of physiological functions attributed to CCK-BR both within and outside the gastrointestinal system. This absence may be due to compensation by other perhaps redundant hormones and their receptors serving the same function. The effect of disrupting the CCK-BR on gastric parietal and ECL cells on acid production was recently reinforced by Koh et al. (7) by disruption of the gastrin gene, which also reduced the number of chief cells. In addition, there was a decreased rate of proliferation of the colonic mucosa, although without a change in histological appearance (7). The effects on the colonic mucosa are likely to be the result of progastrin and glycine-extended gastrin acting on a non-CCK-BR.

    STRUCTURAL BASIS FOR CCK AND GASTRIN BINDING TO CCK RECEPTORS

GPCRs are activated by a chemically diverse group of ligands, despite their overall structural similarity. Unfortunately, because GPCRs are integral membrane proteins, generation of high-quality crystals necessary for detailed X-ray structural analysis to help explain this observed diversity has so far been unsuccessful. However, using the low-resolution electron cryomicroscopic structure of rhodopsin and sequence comparison of more than 200 GPCRs, a general working model of transmembrane helical orientation, packing, and alignment has been proposed (1), and the usefulness of its basic features has been confirmed by a number of biochemical and molecular genetic mutational studies. From this model, it has been determined that almost all small ligand-interacting amino acids are oriented toward the central, hydrophilic cleft of the receptor. Although the structural features of the transmembrane core of the receptor are becoming clearer, the structure of the more variable and less ordered extracellular surface of GPCRs remains unclear. Peptide ligands are thought to interact with amino acids at the top of the transmembrane domains and in the less well-characterized extracellular loops of GPCRs (3).

A study examining 58 chimeric receptors, in which one to four divergent amino acids in the transmembrane domain of the CCK-BR were replaced with the corresponding amino acids from the CCK-AR, identified only a single residue, Ser131, at the top of TM III, conferring approximately sixfold subtype selectivity for the peptide agonist gastrin vs. CCK-8 (9).

Elegant studies examining the extracellular NH2 terminus of the CCK-AR, utilizing first a 42-amino acid NH2-terminal truncation of the human CCK-AR and subsequently site-directed mutants in the region near the top of TM I, suggested the interaction of amino acid residues Trp39 and Gln40 with CCK (Fig. 2). Further binding between wild-type, Trp39-Phe and Gln40-Asn mutant CCK-AR and a series of NH2-terminally modified CCK analogs that were applied to a model of the CCK-AR (based on data from bacteriorhodopsin, rhodopsin, and the beta -adrenergic receptors) suggested that the NH2-terminal moiety of CCK-8 interacts via hydrogen bonding to Trp39 and Gln40 (6).

The interaction of CCK with the CCK-AR was further modeled in a study (24) describing the separate single amino acid mutations of Lys105-Val and Arg337-Val (Fig. 2) in the CCK-AR expressed in CHO cells that resulted in a loss in CCK-8-stimulated Ca2+ release. The loss of Ca2+ release in the cells expressing CCK-AR Lys105-Val and Arg337-Val was attributed to the loss of interaction with CCK at Tyr(SO3H)52 and Asp57 (Fig. 1; CCK-58), respectively (24).

A study of the rat CCK-BR using chimeric CCK-AR/CCK-BR to determine the structural basis of CCK-BR subtype selectivity for gastrin vs. CCK-8 identified the importance of the second extracellular loop. Site-directed mutagenesis of the second extracellular loop suggested that a segment of five amino acids (near Cys205, which putatively forms a disulfide bridge with Cys127 at the top of TM III) (Fig. 2) was important for gastrin selectivity (19). Independent human chimeric CCK-AR/CCK-BR studies based on exon shuffling of the respective receptor genes also demonstrated the importance of this area near the top of TM III for conferring high gastrin affinity (32).

    CCK RECEPTOR REGULATION

Physiological systems regulate signaling between extracellular stimuli and cellular GPCRs at several levels, including secretion, clearance, and degradation of the signaling molecule; desensitization, endocytosis, and downregulation of the receptor; and modulation of postreceptor effectors. Desensitization, the earliest process in the attenuation of GPCR signaling, has been best characterized for rhodopsin and beta -adrenergic receptors, where phosphorylation by a family of G protein-coupled receptor kinases (GRK) and second messenger kinases such as protein kinase A (PKA) [and for some other receptors, protein kinase C (PKC)] leads to the uncoupling of the receptors from their respective G proteins. For the CCK-AR, CCK at supraphysiological concentrations causes rapid phosphorylation by both PKC and GRK of native receptors in pancreatic acini and by PKC alone in recombinant transfected CHO cells (14). CCK-AR phosphorylation accounts for ~50% of the first 1- to 2-min component of desensitization of the CCK-AR expressed in CHO cells, with longer-term and near-complete attenuation attributed to internalization to either a site of "insulation" indistinguishable from the plasma membrane in pancreatic acinar cells or to a deeper endocytic compartment in CHO cells (20). Internalization is independent of the state of phosphorylation and the COOH-terminal tail of the CCK-AR (18, 20), unlike the CCK-BR, which is ~80% dependent on potential Ser/Thr residues in the COOH terminus for internalization (18). Fusion of the green fluorescent protein (GFP) from jellyfish to the COOH terminus of the CCK-AR did not alter ligand affinity, signal transduction, expression, or internalization and allowed for real-time simultaneous studies of both fluorescent ligand and receptor trafficking. Studies of CCK-AR/GFP stably expressed in CHO, NIH/3T3, and HeLa cells and transiently expressed in COS-1 cells demonstrated that receptor internalization was predominantly ligand dependent, except in NIH/3T3 cells, where it was constitutive but inhibitable by the peptide and nonpeptide antagonists CCK-(27---32) amide and L-364,718, respectively. The fluorescent ligand, Cy3.29-CCK-8, dissociated from the receptor with a half time of ~25 min, with subsequent recycling of the receptor back to the cell membrane in ~60 min, while only Cy3.29-CCK-8 sorted to the lysosomes (23). GFP tagging should be applicable for the study in real time of the regulation and trafficking of other GPCR receptors and their ligands in living cells.

    CONCLUSIONS
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Abstract
Introduction
Conclusions
References

The gastrointestinal system consists of a variety of tissues, each with a specific function necessary for the effective handling of a meal. The coordination of these separate functions is achieved in large part by molecules of neuroendocrine origin that regulate their target cells through GPCR-mediated signaling. The large number of GPCR families and their subtypes allows for a specificity necessary for the complexity of the task. Recent advances in the identification and cloning of many of the GPCRs have accelerated our understanding of how the physiological processes within the gastrointestinal system are regulated. GPCRs share structural features and signal-transduction mechanisms that allow for some generalization across families; however, there are significant differences even between subtypes and the cell system in which they are expressed that necessitate the specific analysis of individual receptors. The understanding of CCK receptors as a single family of GPCRs that is representative of numerous other GPCR families widely distributed throughout the gastrointestinal system has benefitted from the early development of radioimmunoassays for their peptide ligands and more recently from radioligands and specific antagonists. Most recently, the molecular cloning of their cDNAs and genes has allowed new approaches for determining receptor localization, the structural basis for receptor ligand and effector interactions in transfected cell systems, and the assignment of physiological roles through their molecular manipulation in transgenic animals. Ultimately these new approaches to the understanding of GPCRs hold the promise of improved diagnosis and therapy of diseases resulting from receptor hypo- and hyperfunctioning states, some of which may be gene based.

    FOOTNOTES

* First in a series of invited articles on G Protein-Coupled Receptors in Gastrointestinal Physiology.

Address reprint requests to Bldg. 10, Rm. 9C103, National Institutes of Health, Bethesda, MD 20892-1804.

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AJP Gastroint Liver Physiol 274(4):G607-G613