Calcitonin gene-related peptide receptor antagonist human CGRP-(8-37).
From this study, we predicted that the human calcitonin gene-related peptide (hCGRP) fragment hCGRP-(8-37) would be a selective antagonist for CGRP receptors but an agonist for calcitonin (CT) receptors. In rat liver plasma membrane, where CGRP receptors predominate and CT appears to act through these receptors, hCGRP-(8-37) dose dependently displaced 125I-[Tyr0]rat CGRP binding. However, hCGRP-(8-37) had no effect on adenylate cyclase activity in liver plasma membrane. Furthermore, hCGRP-(8-37) inhibited adenylate cyclase activation induced not only by hCGRP but also by hCT. On the other hand, in LLC-PK1 cells, where calcitonin receptors are abundant and CGRP appears to act via these receptors, the bindings of 125I-[Tyr0]rat CGRP and 125I-hCT were both inhibited by hCGRP-(8-37). In contrast to liver membranes, interaction of hCGRP-(8-37) with these receptors led to stimulation of adenosine 3',5'-cyclic monophosphate (cAMP) production in LLC-PK1 cells, and moreover, this fragment did not inhibit the increased production of cAMP induced not only by hCT but also by hCGRP. Thus hCGRP-(8-37) appears to be a useful tool for determining whether the action of CGRP as well as that of CT is mediated via specific CGRP receptors or CT receptors.
Chiba
T
T
Third Department of Internal Medicine, Kobe University School of Medicine, Japan.
Yamaguchi
A
A
Yamatani
T
T
Nakamura
A
A
Morishita
T
T
Inui
T
T
Fukase
M
M
Noda
T
T
Fujita
T
T
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002116:Calcitonin / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide; D002462:Cell Membrane / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D009479:Neuropeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*
D009479:Neuropeptides; D010446:Peptide Fragments; D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface; C058636:calcitonin gene-related peptide (8-37); D002116:Calcitonin; D005934:Glucagon; D000262:Adenylyl Cyclases; D015740:Calcitonin Gene-Related Peptide; D004837:Epinephrine