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.
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