Identification of MrgX2 as a human G-protein-coupled receptor for proadrenomedullin N-terminal peptides.
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.
Kamohara
Masazumi
M
Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 305-8585, Japan. kamohara@yamanouchi.co.jp
Matsuo
Ayako
A
Takasaki
Jun
J
Kohda
Masanobu
M
Matsumoto
Mitsuyuki
M
Matsumoto
Shun-ichiro
S
Soga
Takatoshi
T
Hiyama
Hideki
H
Kobori
Masato
M
Katou
Masao
M
D000313:Adrenal Medulla / Q000378:metabolism; D053607:Adrenomedullin / Q000031:analogs & derivatives; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D005727:Ganglia, Spinal / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins; D009479:Neuropeptides / Q000378:metabolism; D009928:Organ Specificity; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C480039:MRGPRX2 protein, human; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010446:Peptide Fragments; D010455:Peptides; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C099323:cortistatin; C108283:proadrenomedullin (9-20); D053607:Adrenomedullin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; D002118:Calcium