Identification and characterization of five-transmembrane isoforms of human vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptors.

The seven-transmembrane (7TM) G-protein-coupled neuroendocrine receptors VPAC1 (HGNC approved gene symbol VIPR1) and VPAC2 (HGNC approved gene symbol VIPR2) are expressed in different tissues and involved in the regulation of important biological functions. We now report the identification and characterization of novel five-transmembrane(5TM) forms of both human VPAC1 and human VPAC2. These alternatively spliced variant mRNAs result from the skipping of exons 10/11, spanning the third intracellular loop, the fourth extracellular loop, and the transmembrane regions 6 and 7, producing in-frame 5TM receptors predicted to lack a G-protein-binding motif. RT-PCR showed that these 5TM receptors are differentially expressed in transformed and normal cells. Translation of the 5TM protein was demonstrated by transfection and expression in CHO cells. Following agonist stimulation, differential signaling of the 7TM versus 5TM forms was shown both for the activation of adenylate cyclase and for tyrosine phosphorylation. The identification of these splice variants in various cells and their expression and differential signal transduction compared to the 7TM form suggest that these novel receptors have biological relevance.