ALTERNATIVE SPLICING IN THE N-TERMINAL EXTRACELLULAR DOMAIN OF THE PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) RECEPTOR MODULATES RECEPTOR SELECTIVITY AND RELATIVE POTENCIES OF PACAP-27 AND PACAP-38 IN PHOSPHOLIPASE-C ACTIVATION

Pituitary adenylate cyclase-activating polypeptide (PACAP)-27 and PACA P-38 are neuropeptides of the vasoactive intestinal peptide/secretin/g lucagon family. We previously described alternative splicing of the re gion encoding the third intracellular loop of the PACAP receptor gener ating six isoforms with differential signal transduction properties (S pengler, D., Waeber, C., Pantaloni, C., Holsboer, F., Bockaert, J., Se eburg, P. H., and Journot, L. (1993) Nature 365, 170-175). In addition , we demonstrated that She potencies of the two forms of PACAP are sim ilar for adenylate cyclase stimulation, whereas PACAP-38 is more poten t than PACAP-27 in phospholipase C activation. In the present work, we document the existence of a new splice variant of the PACAP receptor that was characterized by a 21-amino-acid deletion in the N-terminal e xtracellular domain. We demonstrate that this domain modulates recepto r selectivity with respect to PACAP-27 and -38 binding and controls th e relative potencies of the two agonists in phospholipase C stimulatio n.