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Distribution of the VPAC₂ Receptor in Peripheral Tissues of the Mouse

Division of Neuroscience (A.J.H., W.J.S., C.F.M.), School of Biomedical and Clinical Laboratory Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9JZ; and Institute of Pathology (B.W., M.G., J.C.R.), University of Berne, CH-3010 Berne, Switzerland

Address all correspondence and requests for reprints to: Prof. Anthony J. Harmar, Division of Neuroscience, School of Biomedical and Clinical Laboratory Sciences, University of Edinburgh, 1 George Square, Edinburgh, United Kingdom EH8 9JZ. E-mail: tony.harmar{at}ed.ac.uk.

The neuropeptide vasoactive intestinal peptide (VIP) exerts its actions through two structurally related G protein-coupled receptors (VPAC₁ and VPAC₂). Pituitary adenylate cyclase-activating polypeptide (PACAP) is also a potent agonist of VPAC₁ and VPAC₂ receptors as well as of a third, PACAP-specific receptor (PAC₁). We report here the distribution of the VPAC₂ receptor in peripheral tissues of the mouse, determined by receptor autoradiography using [¹²⁵I]VIP and the selective VPAC₂ receptor agonist [¹²⁵I]Ro25-1553 in wild-type and VPAC₂ receptor-null mice. In addition, displacement experiments with the VPAC₂-selective agonist Ro25-1553 and the VPAC₁-selective agonist [K¹⁵,R¹⁶,L²⁷]VIP(1–7)/GRF(8–27) were performed using the universal radioligand [¹²⁵I]VIP. The VPAC₂ receptor is found predominantly in smooth muscle (in blood vessels and in the smooth muscle layers of the gastrointestinal and reproductive systems), the basal part of the mucosal epithelium in the colon, lung, the vasculature of the kidney, adrenal medulla, and retina. Unexpectedly, the receptor was also present in thyroid follicular cells and acinar cells of the pancreas, tissues that have not been found to express the receptor in other species, and in very large amounts in the lung. Our data suggest novel functions of the VPAC₂ receptor and additional potential therapeutic uses of drugs acting at the receptor (including the treatment of erectile dysfunction), but our results also indicate that caution should be exercised in using the mouse as an animal model for the evaluation of VIP analogs intended for diagnostic or therapeutic use in man.

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