A Natural Variant Type II G Protein-coupled Receptor for Vasoactive Intestinal Peptide with Altered Function

The vasoactive intestinal peptide (VIP) and its G protein-coupled receptors VPAC(1) and VPAC(2) prominently mediate diverse physiological functions in the neural, endocrine, and immune systems. A deletion variant of mouse VPAC(2) has been identified in immune cells that lacks amino acids 367 - 380 at the carboxyl-terminal end of the seventh transmembrane domain. When expressed at equivalent levels in a human Jurkat T cell line, which has very low endogenous expression of human VPAC(1) and VPAC(2), wild-type and deletion-variant VPAC(2) bound the same amount of I-125-VIP with similar affinity. Unlike wild-type VPAC(2), however, deletion-variant VPAC(2) did not transduce VIP-elicited increases in intracellular concentration of cyclic AMP, chemotaxis, or suppression of generation of interleukin-2. Natural deletion of part of the last transmembrane domain of VPAC(2) thus abrogates signaling functions without apparent alterations of expression or ligand binding.