The calcitonin receptor-like receptor/receptor activity-modifying protein 1 heterodimer can function as a calcitonin gene-related peptide-(8-37)-sensitive adrenomedullin receptor.
The receptor activity-modifying protein (RAMP)/calcitonin receptor-like (CRL) receptor heterodimer is thought to function as a receptor for either a calcitonin gene-related peptide (CGRP) (CRL receptor/RAMP1) or adrenomedullin (CRL receptor/RAMP2 or -3), depending on the RAMP isoform present. We examined the receptor specificity of adrenomedullin-induced increases in cAMP in human embryonic kidney (HEK)293 cells coexpressing human CRL receptor and human RAMP1 or RAMP2. In cells expressing CRL receptor/RAMP1, adrenomedulin-induced increases in cAMP were comparable to those induced by alpha-CGRP, and the CGRP receptor antagonist alpha-CGRP-(8-37), but not the adrenomedullin receptor antagonist adrenomedullin-(22-52), blocked the adrenomedullin-evoked responses. Cells expressing CRL receptor/RAMP2 responded more selectively to adrenomedullin; in this case, the effect was blocked by adrenomedullin-(22-52) but not by alpha-CGRP-(8-37). Real-time quantitative polymerase chain reaction confirmed that cotransfection of CRL receptor and RAMP1 had no effect on the endogenous expression of RAMP2. Thus, CRL receptor/RAMP1 likely functions as an adrenomedullin receptor as well as a CGRP receptor, which may explain why many of the actions of adrenomedullin are potently antagonized by alpha-CGRP-(8-37).
First Department of Internal Medicine, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Yasuko
Y
Nagoshi
Kenji
K
Kuwasako
Kaoru
K
Ito
Tomohiko
T
Uemura
Johji
J
Kato
Kazuo
K
Kitamura
Tanenao
T
Eto
D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D058286:Calcitonin Receptor-Like Protein; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*; D014162:Transfection
C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; C545502:RAMP1 protein, human; C545503:RAMP2 protein, human; D012333:RNA, Messenger; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin; D018000:Receptors, Peptide; C104782:adrenomedullin (22-52); C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide