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A Cloned Frog Vasoactive Intestinal Polypeptide/ Pituitary Adenylate Cyclase-Activating Polypeptide Receptor Exhibits Pharmacological and Tissue Distribution Characteristics of Both VPAC₁ and VPAC₂ Receptors in Mammals¹

European Institute for Peptide Research 23, Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U-413, Centre National de la Recherche Scientifique, University of Rouen (D.A., Y.A., S.J., H.V.), 76821 Mont-Saint-Aignan, France; and Institut National de la Recherche Scientifique-Santé, Université du Québec (A.F.), Pointe Claire, Canada H9R 1G6

Address all correspondence and requests for reprints to: Dr. H. Vaudry, European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U-413, Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont-Saint-Aignan, France. E-mail: hubert.vaudry{at}univ-rouen.fr

Three receptor subtypes for the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have been identified in mammals: the PAC₁ receptor (PAC₁-R) which is selectively activated by PACAP, and two VPAC receptors (VPAC₁-R and VPAC₂-R), which are equally stimulated by PACAP and VIP. The structures of PACAP and VIP have been well conserved during evolution, but little is known about VIP/PACAP receptors in nonmammalian species. An amphibian VIP/PACAP receptor complementary DNA (cDNA) has been cloned and characterized from a frog (Rana ridibunda) pituitary cDNA library. The predicted protein contains seven putative transmembrane domains and exhibits the highest sequence identity (65%) with the human VPAC₁-R. The cloned cDNA was transiently expressed in LLC-PK1 cells, and its pharmacological profile was determined in comparison with the human VPAC₁-R. Both PACAP and VIP stimulated cAMP accumulation through the cloned receptor with an EC₅₀ of about 30 nM. In contrast, secretin, at concentrations that stimulate the human VPAC₁-R, had no effect on cAMP production. RT-PCR analysis revealed the widespread distribution of this frog VIP/PACAP receptor in peripheral tissues. In situ hybridization histochemistry using a complementary RNA probe showed that the receptor gene is highly expressed in several hypothalamic and thalamic nuclei and to a lesser extent in the pallium and striatum. In the pituitary, the highest messenger RNA levels were detected in the distal lobe. Taken together, these data show that the cloned frog receptor shares several common features with both the VPAC₁-R and VPAC₂-R of mammals; the frog receptor exhibits the highest sequence identity with mammalian VPAC₁-R, but the lack of effect of secretin and the brain distribution of the receptor are reminiscent of the characteristics of the mammalian VPAC₂-R. The sequence of the frog receptor should thus prove useful to decipher the structure-activity relationships of the VIP/PACAP receptor family.

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