This is the first in a series of reviews written by committees of experts of the Nomenclature Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR). A listing of all articles in the series and the Nomenclature Reports from IUPHAR published in Pharmacological Reviews can be found at http://www. GuideToPharmacology.org. This website, created in a collaboration between the British Pharmacological Society (BPS) and the International Union of Basic and Clinical Pharmacology (IUPHAR), is intended to become a "one-stop shop" source of quantitative information on drug targets and the prescription medicines and experimental drugs that act on them. We hope that the Guide to Pharmacology will be useful for researchers and students in pharmacology and drug discovery and provide the general public with accurate information on the basic science underlying drug action.Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are members of a superfamily of structurally related peptide hormones that includes glucagon, glucagon-like peptides, secretin, gastric inhibitory peptide (GIP) and growth hormone-releasing hormone (GHRH). VIP and PACAP exert their actions through three GPCRs -PAC1, VPAC1 and VPAC2 -belonging to class B (also referred to as class II, or secretin receptor-like GPCRs). This family comprises receptors for all peptides structurally related to VIP and PACAP, and also receptors for parathyroid hormone, corticotropin-releasing factor, calcitonin and related peptides. PAC1 receptors are selective for PACAP, whereas VPAC1 and VPAC2 respond to both VIP and PACAP with high affinity. VIP and PACAP play diverse and important roles in the CNS, with functions in the control of circadian rhythms, learning and memory, anxiety and responses to stress and brain injury. Recent genetic studies also implicate the VPAC2 receptor in susceptibility to schizophrenia and the PAC1 receptor in post-traumatic stress disorder. In the periphery, VIP and PACAP play important roles in the control of immunity and inflammation, the BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 How to cite: Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR et al. (2012). control of pancreatic insulin secretion, the release of catecholamines from the adrenal medulla and as co-transmitters in autonomic and sensory neurons. This article, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittee on receptors for VIP and PACAP, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions and their likely physiological roles in health and disease. More detailed information has been incorporated into newly revised pages in the IUPHAR database (http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=67). LINKED ARTICLESThis article is part of a themed section o...
Alternative splicing of two exons of the rat pituitary adenylate cyclase activating polypeptide (PACAP) receptor gene generates four major splice variants that are differentially expressed in specific tissues and variably coupled to intracellular second messengers. To evaluate the potential implications of these findings in human physiology, the human PACAP receptor gene was cloned. Alternative splicing about two exons of the gene allowed for four major splice variants that were subsequently identified on cDNA cloning. Each of the four splice variant cDNAs (null, SV-1, SV-2, and SV-3) was stably expressed in NIH/3T3 cells at similar receptor densities. For each splice variant, PACAP (both PACAP-38 and PACAP-27) had similar affinity and potency for stimulating either adenylate cyclase or phospholipase C. However, each receptor splice variant differed in their ligand-stimulated maximal response (efficacy) for total inositol phosphate accumulation with the SV-2 showing the greatest efficacy, followed by the null, SV-1, and SV-3 splice variants. Therefore, unlike the rat, PACAP binds and stimulates signal transduction with nearly equal affinity and potency for each of the receptor splice variants although with varying efficacy for the stimulation of phospholipase C. These results suggest a novel and potentially important mechanism for a single hormone to not only couple to dual signal transduction cascades but also elicit tissue-specific differential activation of phospholipase C in humans.
Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide belong to the vasoactive intestinal peptide (VIP)/secretin/glucagon family of peptides, Interacts with a distinct hig-afflnity receptor (type I receptor) on a number of tissues. These PACAP type I receptors have a hh affinity for PACAP and a low affhity for VIP and are present in the hypothalamus and anterior pituiltary, where they regulate the release of adrenocorticotropin, luteinizing hormone, growth hormone, and prolactin, and in the adrenal medulla, where they regulate the release of epinephrine. Type I PACAP receptors are also present in high concentrations in tticular germ ceils, where they may re spermatogenesis, and some trnsformed cefl lines, such as the rat pancreatic acinar carinoma cel AR4-2J. Here we report the moleular cloin and functional expression ofthe PACAP type I receptor isolated from an AR4-2J cell cDNA library by cross-hybridization screening with a rat VIP receptor cDNA. (4); and in the gastrointestinal tract, where they cause smooth muscle relaxation and secretion (11)(12)(13). Type I receptors have also been described on cultured rat astrocyes (14), a rat adrenal pheochromocytoma cell line, PC12H (9), a rat pancreatic acinar carcinoma cell line, AR4-2J (15), and a human neuroblastoma cell line, .Affinity crosslinking studies of type I PACAP receptors on bovine brain membranes demonstrate a 57-kDa molecular species that is modulated in its affinity for PACAP by guanine nucleotides (17) and suggest its membership in the guanine nucleotide-binding regulatory protein (G protein)-coupled family ofreceptors similar to the recently cloned VIP (18) and secretin receptors (19).Further knowledge of the molecular structure of the PACAP type I receptor and its gene would enhance our understanding of its distribution, function, and regulation. We describe here the identification of cDNA clones resulting from cross-hybridization screening of a cDNA library constructed from the rat pancreatic carcinoma cell line AR4-2J with a rat VIP receptor cDNA probe.t These clones encode a protein that has an affinity for PACAP-38, PACAP-27, and VIP consistent with the type I PACAP receptor pharmacology, has a high degree of homology to both the VIP and secretin receptors, and mediates PACAP-stimulated accumulation of intracellular cAMP. MATERIALS AND METHODScDNA Library Construction and Isolation of cDNA Clones. A cDNA library was constructed from AR4-2J cells as described previously (20). The library (%7 x 105 plaques) was screened with a 32P-labeled, randomly primed probe (21) corresponding to the complete coding region of the rat VIP receptor cDNA (18) that was PCR cloned from rat pancreatic cDNA. The library was initially screened under conditions of low and later high stringency [three 20-min washes at 37°C with 2x SSC/0.1% SDS for low-stringency screening and three 20-min washes at 420C with 0.1x SSC/0.1% SDS for high-stringency screening (lx SSC = 150 mM NaCl/15 mM sodium citrate, pH 7.0)] (22). Several clones that hybridi...
The regulation of acid secretion has been divided into cephalic and peripheral (gastric and intestinal) phases (1). The cephalic phase of gastric acid secretion originates in the central nervous system and impacts the hypothalamus; signals travel via the vagus nerve to the myenteric plexuses of the gastric mucosa. In the succeeding neural network, a variety of secondary neurons signal the gastric fundic and antral epithelia to influence gastric acid secretion by either primary or secondary action, namely, direct effects on parietal cells or gastric epithelial endocrine cells. The peripheral phase of acid secretion regulation involves local signaling within a variety of endocrine cells, transmitting regulatory information to the secretory cells of the gastric mucosa; the peripheral phase is more limited than the cephalic phase in terms of the possible mediators involved (2). Studies of isolated gastric endocrine cells have proved useful in defining the interactions of various signals in the regulation of gastric acid secretion, but such studies must be placed in context when considering their physiological implications. The isolated rabbit gastric gland is a more integrated model than that provided by isolated cells.With the isolation and purification (to between 85% and 95%) of functional enterochromaffin-like (ECL) cells from the rat gastric mucosa, a variety of receptors has been defined on this cell type. This has been done by measurement of calcium signals under superfusion conditions using video microscopy, and by histamine or pancreostatin release by radioimmunoassay under static conditions (3-5). When histamine release is measured in a static system, cross-talk is a problem. Superfusion of isolated, enriched ECL cells while measuring responses of intracellular calcium [Ca 2+ ] i eliminates cross-talk between possible contaminating gastric endocrine cells. Nevertheless, few (if any) inconsistencies have been found between the results of video-imaging and release measurements in this particular preparation. In this preparation, there are less than 2% D cells, and the addition of somatostatin antibody has not affected either calcium signaling or histamine release in response to a variety of agonists (3, 4).Histamine, released from ECL cells, is the most important direct stimulant of acid secretion, as shown by the broad efficacy of histamine-2 receptor antagonists as full inhibitors of gastrin and partial inhibitors of vagally stimulated acid secretion (6). The involvement of ECL cells in mediation of the cephalic (neural) phase of gastric acid secretion has been less clear. The atropine sensitivity of cephalic stimulation of acid secretion pointed
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