Peptide Receptors and Signal Transduction in the Digestive Tract

Laburthe, Marc; Kitabgi, Patrick; Couvineau, Alain; Amiranoff, B.

doi:10.1007/978-3-642-77814-8_5

Cited by 17 publications

(12 citation statements)

References 233 publications

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“…This work demonstrates that replacement of histidine 178 by arginine in the human VIP1 receptor results in constitutive activation of the receptor with respect to cAMP production, which constitutes its signaling pathway (35). In contrast, the wild type VIP receptor appears to be truly silent in the absence of VIP.…”

Section: Discussionmentioning

confidence: 80%

Constitutive Activation of the Human Vasoactive Intestinal Peptide 1 Receptor, a Member of the New Class II Family of G Protein-coupled Receptors

Gaudin

Maoret

Couvineau

et al. 1998

Journal of Biological Chemistry

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The human vasoactive intestinal peptide (VIP) 1 receptor belongs to the new class II subfamily of G protein-coupled receptors. Specific change by mutagenesis of a strictly conserved histidine into arginine at position 178 of the human VIP1 receptor resulted in its constitutive activation with respect to cAMP production. Transfection of the H178R mutant into COS cells resulted in a 3.5-fold increase in the cAMP level as compared with cells transfected with the wild type receptor or the vector alone. This increase was proportional to the amount of transfected cDNA. The H178R mutant exhibited an otherwise normal cAMP response to VIP as well as a dissociation constant similar to that of the wild type receptor. Other mutants at position 178 such as H178K, H178A, and H178D were not constitutively activated. They were otherwise expressed at the cell surface of transfected nonpermeabilized cells. Double mutants were then constructed in which the H178R mutation was associated with a point mutation in the the N-terminal extracellular domain that totally abolished VIP binding or VIP-stimulated cAMP production, i.e. E36A or D68A. The corresponding double mutants H178R/ E36A and H178R/D68A were no longer constitutively activated. A control double mutant (H178R/D132A) with an unaltered dissociation constant for VIP and cAMP response to VIP was still constitutively activated. Our findings demonstrate that constitutive activation of the VIP1 receptor by mutation of His 178 into R requires the functional integrity of the N-terminal extracellular VIP binding domain. They might provide interesting generalities about the activation process of G protein-coupled receptors.G protein-coupled receptors with seven transmembrane domains, which constitute a large multigene family of eucaryotic proteins, interact with alkaloids, biogenic amines, peptides, glycoprotein hormones, light, and odorants (1). During the past few years, a subfamily of the superfamily of G protein-coupled receptors has emerged that shares the seven-membrane-spanning domain topography but has a low overall amino acid sequence homology (Ͻ20%) with other members of the superfamily (2, 3). This subfamily, now referred to as the class II G protein-coupled receptor family, comprises receptors for a family of structurally related peptides that includes vasoactive intestinal peptide (VIP), 1 pituitary adenylate cyclase-activating polypeptide, glucagon, secretin, glucagon-like peptide 1, gastric inhibitory polypeptide, and growth hormone-releasing peptide and more unexpectedly also comprises receptors for parathyroid hormone (PTH) and calcitonin (2-4). Recent studies have extended this subfamily (3) with the discovery of subtypes of the above mentioned receptors as well as two new members having an extraordinary long N-terminal domain: the putative EGF module-containing, mucin-like hormone receptor EMR1 (5) and the leukocyte activation antigen CD97 (6).Class II G protein-coupled receptors for peptides have homologies ranging between 30 and 50% and among several common struct...

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Section: Discussionmentioning

confidence: 80%

Constitutive Activation of the Human Vasoactive Intestinal Peptide 1 Receptor, a Member of the New Class II Family of G Protein-coupled Receptors

Gaudin

Maoret

Couvineau

et al. 1998

Journal of Biological Chemistry

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“…Although several studies have long been reported regarding the pharmacology of analogs of VIP and related peptides (40 -43), no systematic evaluation of the functional and structural role of every residues of VIP has been yet performed since the cloning of the two VIP receptor subtypes VPAC 1 and VPAC 2 (44). Moreover most previous studies were performed using VIP receptors from rodents although it is clear that there are important differences between species in the pharmacology of VIP receptors (8,15).…”

Section: Discussionmentioning

confidence: 99%

“…Chicken [Arg 16 ]secretin, although it discriminates between rat VPAC 1 and VPAC 2 receptors, has a high affinity for rat secretin receptor (59). Moreover, it has a rather weak affinity for the human VPAC 1 receptor (60), in line with the important differences between species in the pharmacology of VPAC 1 receptors (15,44 ]VIP (1-7)/GRF (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) has an important selectivity for VPAC 1 receptor but its possible interaction with GRF receptors was not directly evaluated (61). In this context, the highly selective human VPAC 1 receptor agonist developed in this study by rationale combination of three mutations in VIP itself constitutes henceforth the most operative pharmacological tool derived from VIP for characterizing VPAC 1 receptor-mediated events.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Residues for Interaction of Vasoactive Intestinal Peptide with Human VPAC1 and VPAC2Receptors and Development of a Highly Selective VPAC1Receptor Agonist

Nicole

Lins

Rouyer‐Fessard

et al. 2000

Journal of Biological Chemistry

159

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The widespread neuropeptide vasoactive intestinal peptide (VIP) has two receptors VPAC 1 and VPAC 2 . Solid-phase syntheses of VIP analogs in which each amino acid has been changed to alanine (Ala scan) or glycine was achieved and each analog was tested for: (i) threedimensional structure by ab initio molecular modeling; (ii) ability to inhibit 125 ]VIP analog which constitutes the first highly selective (>1,000-fold) human VPAC 1 receptor agonist derived from VIP ever described. The vasoactive intestinal peptide (VIP)1 is a prominent neuropeptide with wide distribution in both peripheral and central nervous systems and a large spectrum of biological actions in mammals (1, 2). VIP-containing nerves and VIP effects have been described in digestive tract, cardiovascular system, airways, reproductive system, immune system, endocrine glands, and brain (1). Besides its short-term actions on exocrine secretions, hormone release, muscle relaxation, and metabolism (1, 2), VIP has been also characterized as a growth regulator for fetuses and tumor cells and during embryonic brain development (3). There are recent evidences for an important role of VIP in the perception of pain (4) and suppression of inflammation (5). Finally, VIP has been involved in diseases such as the watery diarrhea syndrome and clinical applications of VIP have been already suggested in impotence, asthma, lung injury, a variety of tumors and neurodegenerative diseases (1-3).VIP belongs to a large family of structurally related peptides (2, 6, 7) that comprises VIP, pituitary adenylate cyclase-activating peptide PACAP-27, and its C-terminal extended form PACAP-38, secretin, glucagon, and glucagon-like peptides-1 and -2, gastric inhibitory polypeptide, peptide histidine methionine amide, growth hormone-releasing factor (GRF), and peptides isolated from the venom of the Gila Monster. VIP and PACAP are the most closely related peptides in terms of structure and function (2, 6). They share two common receptors, VPAC 1 and VPAC 2 , which display high affinity for both VIP and PACAP (2,8). These receptors together with receptors for VIP-related peptides (see above) clearly constitute an original subfamily within the superfamily of G protein-coupled receptors (2, 9, 10). This subfamily referred to as class II (2) also comprises receptors for parathyroid hormone, calcitonin, corticotropin-releasing factor, and the so called EGF-TM7 receptors (11). Class II family of receptors for peptides display several common properties including large N-terminal extracellular domains containing highly conserved cystein residues, N-terminal leader sequences, and complex gene organization with many introns (2).Although the structure-function relationship of VIP receptors, including VPAC 1 and VPAC 2 , has been recently documented (2,9,(12)(13)(14)(15)(16)(17)(18)(19)(20), the structure-function relationship of VIP itself is still poorly understood. Some old studies carried out before the characterization and cloning of VIP receptor subtypes (21-23) indicated that: (i) th...

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“…No hybridization signal was observed in the HT29 cell line, derived from a human colon adenocarcinoma (Fig. 4), and in human liver (data not shown), both devoid of galanin receptors (4). Thus, the heterogeneity of hybridizing species in various tissues may reflect either multiple genes or different alternative RNA splicing forms.…”

Section: Domains Andmentioning

confidence: 91%

“…2 and 3). Galanin exerts its actions via binding to specific membrane receptors (4). Biochemical and molecular studies, performed in brain and pancreas, indicate that the galanin receptor is a glycoprotein of 54 kDa (5)(6)(7) coupled to the inhibitory guanine nucleotide binding (G) protein Gi, identified as Gil, Gi2, and Gi3 in pancreatic 83 cells (8,9).…”

mentioning

confidence: 99%

Molecular cloning of a functional human galanin receptor.

Habert-Ortoli¹,

Amiranoff²,

Loquet³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

322

225

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The ubiquitous neuropeptide galanin controls numerous functions such as endocrine secretions, intestinal motility, and behavioral activities. These regulatory effects of galanin are mediated through the interaction with specific membrane receptors and involve the pertussis toxin-sensitive guanine nucleotide binding proteins Gj/G0 as transducing elements. We report here the isolation of a cDNA coding for a human galanin receptor from a Bowes melanoma cell line cDNA expression library, by using a radioligand binding strategy. The nucleotide sequence ofthe cloned receptor reveals an open reading frame encoding a 349-amino acid protein with seven putative hydrophobic transmembrane domains and significant homology with members of the guanine nucleotide binding protein-coupled neuropeptide receptor family. The cloned receptor expressed in COS cells specifically binds human, porcine, and rat galanin with high affinity (Kd in the nanomolar range) and mediates the galanin inhibition of adenylate cyclase. A 2.8-kb galanin receptor transcript was identified in several human tissues. Cloning of this galanin receptor should enhance our knowledge of its distribution, structure, and function in human physiology and pathophysiology.Galanin, a 29-amino acid neuropeptide (30 amino acids in humans), was originally isolated from pig intestine (1) and later reported to be widely distributed in the central and peripheral nervous systems of numerous species (2). Galanin is unrelated to the other known families of regulatory peptides and, to date, remains the only known member of its own family. It exerts multiple regulatory functions such as (i) control of endocrine and exocrine pancreatic secretions, (ii) regulation of intestinal motility, and (iii) modulation of behavioral, cognitive, and sensory functions such as feeding, learning, memory, and nociception (for reviews, see refs. 2 and 3). Galanin exerts its actions via binding to specific membrane receptors (4). Biochemical and molecular studies, performed in brain and pancreas, indicate that the galanin receptor is a glycoprotein of 54 kDa (5-7) coupled to the inhibitory guanine nucleotide binding (G) protein Gi, identified as Gil, Gi2, and Gi3 in pancreatic 83 cells (8,9). Depending on the target tissue, different pathways for intracellular signaling by galanin are involved: inhibition of adenylate cyclase (10), blockage of voltage-dependent Ca2+ channels (11), and activation of ATP-sensitive K+ channels (12). Structure-activity studies, with galanin fragments (13-15) and chimeric peptides (16,17), generally emphasize the importance of the N-terminal fragment of galanin for the interaction with the peptide receptor. These studies also raise the possibility of the existence of galanin receptor subtypes, an issue that may be properly addressed with the molecular cloning of the galanin receptor.In this context, we describe here the expression cloning of a cDNA encoding a galanin receptor from the human Bowes melanoma cell line (18) (vol/vol) fetal calf serum, 6 mM glutami...

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Peptide Receptors and Signal Transduction in the Digestive Tract

Cited by 17 publications

References 233 publications

Constitutive Activation of the Human Vasoactive Intestinal Peptide 1 Receptor, a Member of the New Class II Family of G Protein-coupled Receptors

Constitutive Activation of the Human Vasoactive Intestinal Peptide 1 Receptor, a Member of the New Class II Family of G Protein-coupled Receptors

Identification of Key Residues for Interaction of Vasoactive Intestinal Peptide with Human VPAC1 and VPAC2Receptors and Development of a Highly Selective VPAC1Receptor Agonist

Molecular cloning of a functional human galanin receptor.

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