Expression and Function of Vasoactive Intestinal Peptide, Pituitary Adenylate Cyclase-Activating Polypeptide, and Their Receptors in the Human Adrenal Gland

Abstract

VIP and pituitary adenylate cyclase-activating polypeptide (PACAP) are two regulatory peptides that possess remarkable amino acid sequence homology and act through common receptors, named PAC1, VPAC1, and VPAC2. PAC1 receptor is selective for PACAP, whereas VPAC1 and VPAC2 receptors bind both VIP and PACAP. We have investigated the expression and function of VIP, PACAP, and their receptors in the zona glomerulosa (ZG), zonae fasciculata and reticularis, and adrenal medulla (AM) of the human adrenal cortex. RT-PCR and RIA detected VIP and PACAP expression exclusively in AM cells. RT-PCR demonstrated the presence of PAC1 mRNA only in AM and of VPAC1 and VPAC2 mRNAs in both ZG and AM cells. VIP and PACAP concentration-dependently increased aldosterone and catecholamine secretion from cultured ZG and AM cells. The catecholamine response to both peptides was higher than the aldosterone response, and the secretagogue action of PACAP was more intense than that of VIP. The aldosterone response of cultured ZG cells to VIP or PACAP was unaffected by the PAC1 receptor antagonist PACAP-(6–38) (PAC1-A), but was significantly decreased by the VPAC1 receptor antagonist [Ac-His1,d-Phe2,Lys15,Arg16]VIP-(3–7),GH-releasing factor-(8–27)-NH2 (VPAC1-A). The catecholamine response of cultured AM cells to VIP was lowered by VPAC1-A and unaffected by PAC1-A; conversely, the catecholamine response to PACAP was reduced by both PAC1-A and VPAC1-A. Simultaneous exposure to both antagonists did not abolish the catecholamine response to PACAP. Collectively, our findings allow us to conclude that in human adrenals 1) VIP and PACAP biosynthesis exclusively occurs in AM cells; 2) ZG cells are provided with functional VPAC1 and VPAC2 receptors, whose activation by VIP or PACAP elicits a moderate aldosterone response; 3) AM cells possess PAC1, VPAC1, and VPAC2 receptors, whose activation evokes a marked catecholamine response; and 4) the catecholamine response to PACAP is more intense than that to VIP, because it is mediated by all subtypes of VIP/PACAP receptors.