Sustained secretion and calcium‐activated gene regulation by PACAP requires expression of the hop domain of the PAC1 receptor

Pituitary adenylate cyclase activating polypeptide (PACAP) is the slow transmitter that mediates sustained catecholamine secretion and stimulus‐secretion‐synthesis coupling for repletion of catecholamine and neuropeptide stores in the adrenal medulla during prolonged metabolic stress (Hamelink et al., PNAS 99 : , 2002). PACAP acts through the PAC1 receptor to effect these calcium‐dependent actions, and the hop cassette of this receptor is specifically required for sustained calcium elevation stimulated by PACAP (Mustafa et al., JBC 2007, PMID 17213203). Here we demonstrate that expression of the bovine PAC1hop receptor in PC12 cells, at levels found in bovine chromaffin cells, significantly enhances both short‐term (0–5 min) and sustained (5–60 min) catecholamine secretion, and enhances transcription from the VIP promoter specifically dependent on the calcium‐response element of this gene. The endogenous PAC1 receptor of PC12 cells supports PACAP‐induced short‐term secretion and stimulation of the VIP gene from its cAMP response element, but not prolonged PACAP‐stimulated secretion and activation of transcription of a PACAP target gene (the VIP promoter) via its calcium response element. These data implicate both PAC1 receptor density, and the specific isoform of the receptor that is expressed, in physiological slow transmitter function of PACAP at the adrenomedullary synapse.