PROADRENOMEDULLIN N-TERMINAL-20 PEPTIDE - MINIMAL ACTIVE-REGION TO REGULATE NICOTINIC RECEPTORS

Citation
M. Mahata et al., PROADRENOMEDULLIN N-TERMINAL-20 PEPTIDE - MINIMAL ACTIVE-REGION TO REGULATE NICOTINIC RECEPTORS, Hypertension, 32(5), 1998, pp. 907-916
Citations number
46
Categorie Soggetti
Peripheal Vascular Diseas
Journal title
ISSN journal
0194911X
Volume
32
Issue
5
Year of publication
1998
Pages
907 - 916
Database
ISI
SICI code
0194-911X(1998)32:5<907:PNP-MA>2.0.ZU;2-C
Abstract
Proadrenomedullin N-terminal 20 peptide (PAMP-[1-20]; ARLDVASEFRKKWNKW ALSR-amide) is a potent hypotensive and catecholamine release-inhibito ry peptide released from chromaffin cells. We studied the mechanism of PAMP action and how its function is linked to structure. We tested hu man PAMP-[1-20] on catecholamine secretion in PC12 pheochromocytoma ce lls and found it to be a potent, dose-dependent (IC50 approximate to 3 50 nmol/L) secretory inhibitor. Inhibition was specific for nicotinic cholinergic stimulation since PAMP-[1-20] failed to inhibit release by agents that bypass the nicotinic receptor. Nicotinic cationic (Na-22( +),Ca-45(2+)) signal transduction was disrupted by this peptide, and p otencies for inhibition of Na-22(+) uptake and catecholamine secretion were comparable. Even high-dose nicotine failed to overcome the inhib ition, suggesting noncompetitive nicotinic antagonism. N- and C-termin al PAMP truncation peptides indicated a role for the C-terminal amide and refined the minimal active region to the C-terminal 8 amino acids (WNKWALSR-amide), a region likely to be alpha-helical. PAMP also block ed (EC50 approximate to 270 nmol/L) nicotinic cholinergic agonist dese nsitization of catecholamine release, as well as desensitization of ni cotinic signal transduction (Na-22(+) uptake). Thus, PAMP may exert bo th inhibitory and facilitatory effects on nicotinic signaling, dependi ng on the prior state of nicotinic stimulation. PAMP may therefore con tribute to a novel, autocrine, homeostatic (negative-feedback) mechani sm controlling catecholamine release.