Vasoactive intestinal peptide (VIP) is a 28-amino acid mediator of the central and peripheral nervous system, that is present at high concentrations in nerves ending in blood vessels, glands, immune organs and epithelial surfaces of the skin, lungs, and gastrointestinal tract. The VIP delivered to these sites is a potent mediator of regional and systemic immune functions and hypersensitivity reactions, as well as diverse other physiological responses. VIP is distinguished from other neuropeptides with immunoregulatory activities by its capacity to affect both B and T cells, influence the homing and regional distribution of lymphocytes, moderate antibody production with isotypic selectivity, and convey signals from mast cells and eosinophils to lymphocytes. The proposed research is designed to increase our understanding of the genetic determinants, protein structure, and cellular properties of human VIP receptors (VIPRs). The recent cloning and sequencing of a full_ length cDNA encoding the high-affinity VIPR of human cultured pre-B lymphocytes and colonic epithelial cells now will permit studies of the structural bases of VIPR functions. The VIPR protein domains required for cellular expression and VIP-binding specificity will be evaluated in mammalian cells transfected with wild-type and various mutant receptors, in parallel with cells bearing native VIPRs. The 5'-regulatory regions of the VIPR gene will be delineated to define controls of expression. Biochemical studies of signal transduction by VIPRs will focus on mechanisms of activation of adenylyl cyclase, association with guanine nucleotide-binding proteins, and VIP-induced desensitization of VIP receptors. The capacity of VIP, natural variants of VIP and antibodies to different epitopes of VIPRs to alter cellular adherence will be examined functionally in lymphocytes and neural cells, and related to changes in the expression of specific surface adhesive proteins. The distribution of the VIPRs in human cells and tissues will be defined with oligonucleotide and antibody probes. A greater knowledge of cellular receptors for VIP may elucidate neural controls of immune, enteric, and endocrine functions and provide useful new approaches to some neuroendocrine and autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Neurology C Study Section (NEUC)
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
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Yadav, Mahesh; Huang, Mei-Chuan; Goetzl, Edward J (2011) VPAC1 (vasoactive intestinal peptide (VIP) receptor type 1) G protein-coupled receptor mediation of VIP enhancement of murine experimental colitis. Cell Immunol 267:124-32
Yadav, Mahesh; Goetzl, Edward J (2008) Vasoactive intestinal peptide-mediated Th17 differentiation: an expanding spectrum of vasoactive intestinal peptide effects in immunity and autoimmunity. Ann N Y Acad Sci 1144:83-9
Goetzl, Edward J; Chan, Robert C; Yadav, Mahesh (2008) Diverse mechanisms and consequences of immunoadoption of neuromediator systems. Ann N Y Acad Sci 1144:56-60
Yadav, Mahesh; Rosenbaum, Jennifer; Goetzl, Edward J (2008) Cutting edge: vasoactive intestinal peptide (VIP) induces differentiation of Th17 cells with a distinctive cytokine profile. J Immunol 180:2772-6
Huang, Mei-Chuan; Miller, Allison L; Wang, Wengang et al. (2006) Differential signaling of T cell generation of IL-4 by wild-type and short-deletion variant of type 2 G protein-coupled receptor for vasoactive intestinal peptide (VPAC2). J Immunol 176:6640-6
Goetzl, Edward J (2006) Hypothesis: VPAC G protein-coupled receptors for vasoactive intestinal peptide constitute a dynamic system for signaling T cells from plasma membrane and nuclear membrane complexes. Regul Pept 137:75-8
Miller, Allison L; Verma, Deepti; Grinninger, Carola et al. (2006) Functional splice variants of the type II G protein-coupled receptor (VPAC2) for vasoactive intestinal peptide in mouse and human lymphocytes. Ann N Y Acad Sci 1070:422-6
Voice, Julia; Donnelly, Samantha; Dorsam, Glenn et al. (2004) c-Maf and JunB mediation of Th2 differentiation induced by the type 2 G protein-coupled receptor (VPAC2) for vasoactive intestinal peptide. J Immunol 172:7289-96
Grinninger, Carola; Wang, Wengang; Oskoui, Kaveh Bastani et al. (2004) A natural variant type II G protein-coupled receptor for vasoactive intestinal peptide with altered function. J Biol Chem 279:40259-62
Voice, Julia K; Grinninger, Carola; Kong, Yvonne et al. (2003) Roles of vasoactive intestinal peptide (VIP) in the expression of different immune phenotypes by wild-type mice and T cell-targeted type II VIP receptor transgenic mice. J Immunol 170:308-14

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