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Pituitary adenylate cyclase-activating polypeptide and adrenomedullary function

Physiology and Pharmacology, University of Southern Denmark, DK-5000 Odense, Denmark

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PITUITARY ADENYLATE CYCLASE-activating polypeptide (PACAP) is an ancestral molecule for a superfamily of 11 hormones and hormone-like substances that have a secretin-containing core in common. These include PACAP, glucagon, glucagon-like peptide-1 and -2, growth hormone-releasing hormone, VIP, peptide histidine methionine, secretin, and glucose-dependent insulinotropic polypeptide (see extensive reviews, Refs. 9, 10). PACAP comes in two variants: a full-length 38-amino acid peptide and a truncated 27-amino acid peptide that is equivalent to the NH₂-terminal amino acids of PACAP-38. PACAP has been identified in many species, including humans, birds, and fish. It is found also in an ancient protochordate, the tunicate (sea squirt, Chelyosoma productum). PACAP is very well conserved across species; thus there is 96% nucleotide identity between human and tunicate PACAP cDNA, suggesting that there has been a high evolutionary pressure to conserve PACAP ever since protochordates and humans separated their evolutionary lines more than 700 million years ago. Despite this, the exact physiological role of PACAP is as yet unclear.

Several PACAP receptors are known. They belong to the G protein-coupled seven-transmembrane segment receptors. There are PACAP-specific receptors (PAC₁-R), which comprise eight splice variants from a single gene. The PAC₁-Rs bind PACAP-27 and PACAP-38 with some variation in affinity among the splice variants, whereas they bind VIP with 100- to 1,000-fold lower affinity than PACAP. In addition, PACAP binds to the VIP receptors VPAC₁-R and VPAC₂-R with the same affinity as VIP. Nearly all the receptors couple to cAMP generation via adenylate cyclase and probably also to the phospholipase C-inositol trisphosphate system. An interesting exception is the PAC₁-R-TM4 splice variant, which activates L-type calcium channels (9, 10).

PACAP was originally isolated from the pituitary gland (8), but it has now been found in virtually every tissue in the body and it has been ascribed functions as a regulator of cell cycle and development, of smooth and cardiac muscle function, of the immune system, of bone metabolism, of endocrine/paracrine function, and of exocrine gland function. PACAP is an ubiquitously distributed neuropeptide in the central nervous system and in peripheral neurons, where it acts as a cotransmitter involved in circadian rhythms and sensory and autonomic function, as for example insulin secretion after glucose ingestion (1). PACAP-deficient mice die if raised in a cool environment because of a reduced ability to develop adaptive thermogenesis (heat formation in brown adipose tissue mediated by norepinephrine-induced uncoupling of cellular respiration from ATP formation; 4).

In the adrenal gland it has been suggested that PACAP is a cotransmitter with acetylcholine at the adrenomedullary synapse and that PACAP may help to couple epinephrine biosynthesis to secretion during metabolic stress (5). In the isolated perfused rat adrenal gland, infusion of PACAP increases adrenal catecholamine output and electrical stimulation leads to an increased catecholamine release, which is inhibited by PAC₁-R blockade (2). The PACAP-induced catecholamine release was inhibited by blockade of L-type calcium channels (3). Furthermore, in vivo infusion of PACAP into anesthetized dogs leads to an increase in adrenal catecholamine output, which is inhibited by a PAC₁ receptor antagonist (6). The study by Lamouche and Yamaguchi (7) in the present issue of American Journal of Physiology-Regulatory, Integrative and Comparative Physiology demonstrates in vivo, in anesthetized dogs, that PACAP is, in fact, released from the adrenal gland in response to splanchnic nerve stimulation, thereby adding an important piece of information to the emerging picture of PACAP as a cotransmitter in the adrenal gland.

Furthermore, Lamouche and Yamaguchi (7) stimulated splanchnic nerve activity by hypotension induced by infusion of sodium nitroprusside in the dog. Their results show that exogenous PACAP facilitated adrenal catecholamine secretion during hypotension. Stimulation of splanchnic nerve activity by insulin-induced hypoglycemia stimulates catecholamine secretion and thereby gluconeogenesis in the liver, which counteracts the hypoglycemia. In PACAP-deficient mice this mechanism is blunted, and insulin-induced hypoglycemia is lethal (5). Thus, in rats, mice, and dogs, PACAP seems to be involved in facilitating and enhancing adrenal catecholamine secretion after a variety of physiological stimuli, thereby supporting an important role for this hormone in the adaptation to a stressful environment.

	FOOTNOTES

Address for reprint requests and other correspondence: O. Skøtt, Physiology and Pharmacology, 21 Winsløwparken,DK-5000 Odense C, Denmark (E-mail: oskott{at}health.sdu.dk).

10.1152/ajpregu.00695.2002

	REFERENCES

TOP ARTICLE REFERENCES

1.   Filipsson, K, Holst JJ, and Ahren B. PACAP contributes to insulin secretion after gastric glucose gavage in mice. Am J Physiol Regul Integr Comp Physiol 279: R424-R432, 2000[Abstract/Free Full Text].

2.   Fukushima, Y, Hikichi H, Mizukami K, Nagayama T, Yoshida M, Suzuki-Kusaba M, Hisa H, Kimura T, and Satoh S. Role of endogenous PACAP in catecholamine secretion from the rat adrenal gland. Am J Physiol Regul Integr Comp Physiol 281: R1562-R1567, 2001[Abstract/Free Full Text].

3.   Fukushima, Y, Nagayama T, Kawashima H, Hikichi H, Yoshida M, Suzuki-Kusaba M, Hisa H, Kimura T, and Satoh S. Role of calcium channels and adenylate cyclase in the PACAP-induced adrenal catecholamine secretion. Am J Physiol Regul Integr Comp Physiol 281: R495-R501, 2001[Abstract/Free Full Text].

4.   Gray, SL, Yamaguchi N, Vencova P, and Sherwood NM. Temperature-sensitive phenotype in mice lacking pituitary adenylate cyclase-activating polypeptide. Endocrinology 143: 3946-3954, 2002[Abstract/Free Full Text].

5.   Hamelink, C, Tjurmina O, Damadzic R, Young WS, Weihe E, Lee HW, and Eiden LE. Pituitary adenylate cyclase-activating polypeptide is a sympathoadrenal neurotransmitter involved in catecholamine regulation and glucohomeostasis. Proc Natl Acad Sci USA 99: 461-466, 2002[Abstract/Free Full Text].

6.   Lamouche, S, and Yamaguchi N. Role of PAC₁ receptor in adrenal catecholamine secretion induced by PACAP and VIP in vivo. Am J Physiol Regul Integr Comp Physiol 280: R510-R518, 2001[Abstract/Free Full Text].

7.   Lamouche, S, and Yamaguchi N. PACAP release from the canine adrenal gland in vivo: its functional role in severe hypotension. Am J Physiol Regul Integr Comp Physiol 284: R588-R597, 2003[Abstract/Free Full Text].

8.   Miyata, A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, and Coy DH. Isolation of a novel 38-residue hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164: 567-574, 1989[Web of Science][Medline].

9.   Sherwood, NM, Krueckl SL, and McRory JE. The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 21: 619-670, 2000[Abstract/Free Full Text].

10.   Vaudry, D, Gonzalez BJ, Basille M, Yon L, Fournier A, and Vaudry H. Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev 52: 269-324, 2000[Abstract/Free Full Text].