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(Hypertension. 1998;32:907-916.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Proadrenomedullin N-Terminal 20 Peptide

Minimal Active Region to Regulate Nicotinic Receptors

Manjula Mahata; Sushil K. Mahata; Robert J. Parmer; ; Daniel T. O'Connor

From the Department of Medicine and Center for Molecular Genetics, University of California at San Diego, and San Diego Veterans Affairs Healthcare System, San Diego, Calif.

Correspondence to Daniel T. O'Connor, MD, Department of Medicine and Center for Molecular Genetics (9111H), University of California at San Diego, 3350 La Jolla Village Dr, San Diego, CA 92161. E-mail doconnor{at}ucsd.edu

Abstract—Proadrenomedullin N-terminal 20 peptide (PAMP-[1-20]; ARLDVASEFRKKWNKWALSR-amide) is a potent hypotensive and catecholamine release–inhibitory peptide released from chromaffin cells. We studied the mechanism of PAMP action and how its function is linked to structure. We tested human PAMP-[1-20] on catecholamine secretion in PC12 pheochromocytoma cells and found it to be a potent, dose-dependent (IC₅₀ 350 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 (²²Na⁺,⁴⁵Ca²⁺) signal transduction was disrupted by this peptide, and potencies for inhibition of ²²Na⁺ uptake and catecholamine secretion were comparable. Even high-dose nicotine failed to overcome the inhibition, suggesting noncompetitive nicotinic antagonism. N- and C-terminal 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 -helical. PAMP also blocked (EC₅₀ 270 nmol/L) nicotinic cholinergic agonist desensitization of catecholamine release, as well as desensitization of nicotinic signal transduction (²²Na⁺ uptake). Thus, PAMP may exert both inhibitory and facilitatory effects on nicotinic signaling, depending on the prior state of nicotinic stimulation. PAMP may therefore contribute to a novel, autocrine, homeostatic (negative-feedback) mechanism controlling catecholamine release.

Key Words: chromogranin • adrenal gland • chromaffin granule • adrenomedullin • catecholamines