PAMP-20 (human)

Proadrenomedullin N-terminal 20 peptide (PAMP[1-20]/PAMP-20) and its truncated analog, PAMP[9-20]/PAMP-12, are endogenous peptides that elicit hypotension through inhibiting catecholamine secretion from sympathetic nerve endings and adrenal chromaffin cells. Although the binding sites for PAMP are widely distributed, the nature of its receptor has been elusive. In an effort to identify potential PAMP receptor(s), we found that a human G-protein-coupled receptor, MrgX2, was specifically activated by PAMP. Although a previous study revealed that MrgX2 was a receptor for cortistatin, a neuropeptide involved in sleep regulation and locomotor activity, our present data indicated that the rank order of the agonistic effect against MrgX2 was "PAMP-12> or =cortistatin>PAMP-20". These activities were confirmed by the inhibition of the forskolin-elevated cAMP accumulation, Ca(2+) mobilization, and [(35)S]guanosine 5'-(gamma-thio)triphosphate binding assays. These findings suggest that MrgX2 couples with not only G(alpha q) but also G(alpha i), consistent with previous reports on the pharmacological profile of PAMP signaling. Furthermore, by immunostaining, we found that MrgX2 was expressed in the adrenal chromaffin cells as well as the dorsal root ganglia. From these results, we concluded that MrgX2 is a potential human PAMP-12 receptor that regulates catecholamine secretion from adrenal glands. The present discovery will eventually lead to a better understanding of the pathophysiological role of proadrenomedullin peptides.

1 The potential vasodilator function of the peptide ghrelin, recently identified as the endogenous ligand of the growth hormone secretagogue orphan receptor (GHS-R), was investigated in human endothelium-denuded internal mammary artery. The peptide endothelin-1 (ET-1) is a potent and long-lasting vasoconstrictor. Comparisons were made with established and putative endogenous vasodilators to determine if any could reverse ET-1-induced vasoconstriction in this vessel. 2 Ghrelin (0.1-300 nM) potently dilated 10 nM ET-1-induced constrictions (pD(2) 8.39+/-0.29; E(MAX) 63+/-5.6%; n=9/14, responders/total). 3 ANP (pD(2) 7.75+/-0.14; E(MAX) 106+/-2.0; n=5/5) and CGRP (pD(2) 8.08+/-0.17; E(MAX) 76+/-15% n=5/6) both produced complete reversal of the constrictor response to ET-1 (E(MAX) not significantly different from 100%, P>0.05 one-sample t-test). 4 The following caused partial reversal of the ET-1 response: Adrenomedullin (n=9/9) and two peptides derived from proadrenomedullin, PAMP-12 (n=6/7) and PAMP-20 (n=9/9) (pD(2) values 7.63+/-0.28, 7.97+/-0.23 and 8.51+/-0.29; E(MAX) 58+/-7.3, 54+/-10 and 51+/-7.8% respectively). Unexpectedly, amylin was only 2 fold less potent than CGRP, although there was less than 50% reversal of the ET-1 constriction (pD(2) 7.86+/-0.30; E(MAX) 41+/-5.4%; n=7/9). CNP (n=6/6) also partially reversed constrictions to ET-1 (E(MAX) 53+/-6.3; pD(2) 8.07+/-0.38). 5 BNP (n=4/5) and PGI(2) (n=6/8) were weak vasodilators, since concentration-response curves failed to reach a maximum within the range tested. PGE(2) caused a small dilatation in some vessels (E(MAX) 17+/-2.1%; pD(2) 8.63+/-0.36; n=4/8). 6 We have demonstrated ghrelin to be an effective, endothelium-independent vasodilator of the long-lasting constrictor ET-1 in human arteries producing responses similar to those of adrenomedullin (P>0.05, ANOVA). British Journal of Pharmacology (2002) 136, 1146-1152

The novel hypotensive peptide, proadrenomedullin N-terminal 20 peptide (PAMP), is processed from the adrenomedullin precursor. Recently, we identified PAMP-12 [PAMP(9-20)] from the porcine adrenal medulla as a major endogenous and biologically active peptide. Using a new, sensitive radioimmunoassay which recognizes the C-terminal region of PAMP-20 [PAMP(1-20)], we investigated the role of PAMP in patients with essential hypertension who had normal renal function, and whether PAMP-12 is present in humans. The mean PAMP plasma concentration, like that of adrenomedullin, was significantly higher in hypertensive [1.51 fmol/mL, standard error of the mean (SEM) 0.09 fmol/mL] than normotensive participants (1.08 fmol/mL, SEM 0.05). The increase in plasma PAMP concentration in patients with organ damage accompanied by hypertension was significantly higher than that in patients without organ damage. The PAMP concentration had a significant positive correlation with mean blood pressure and adrenomedullin concentration. The immunoreactive PAMP in human tissue and plasma was characterized by reverse-phase high-performance liquid chromatography. PAMP-12, as well as PAMP-20, was abundant in the phaeochromocytoma tissue. These findings suggest that PAMP plays some pathophysiological role against the development of essential hypertension.