Characterization of the PAC1 variants expressed in the mouse heart

Pituitary adenylate cyclase-activating polypeptide (PACAP), a pleiotropic neuropeptide, exerts a variety of physiological functions through three types of G protein-coupled receptors, PAC1, VPAC1, and VAPC2. Characterization of the molecular forms of PAC1 in mouse heart revealed the presence of four types of variant receptors harboring the N or S variant in the first extracellular domain (EC1 domain) with or without the HOP1 insert in the third intracellular cytoplasmic loop (IC3 loop). Then, we assessed the binding affinity and ability to stimulate adenylyl cyclase of the PCA1 variant-expressing cells for PACAP. Adenylyl cyclase activation by PACAP was markedly influenced with the variant in the EC1 domain as well as that in the IC3 loop, in spite of a little difference in their binding properties. These data suggest that the combination of EC1 domain variants and IC3 loop variants might account for the diversity of intracellular signaling, which might contribute to multiple functions of PACAP including a role in the cardiovascular system.