Effects of two truncated forms of human calcitonin-gene related peptide: implications for receptor classification.
We investigated the possibility that human alpha-calcitonin-gene related peptide (CGRP)-(8-37) and human beta CGRP-(8-37) show some selectivity as antagonists of CGRP1 and CGRP2 receptor-mediated responses. Bindings assays showed that human alpha CGRP, human alpha CGRP-(8-37) and human beta CGRP-(8-37) showed high affinity (in the nanomolar concentration range) for CGRP receptors expressed in SK-N-MC cells and also in rat brain membrane preparations. Both human alpha CGRP-(8-37) and human beta CGRP-(8-37) were potent antagonists of human alpha CGRP-stimulated cAMP accumulation in SK-N-MC cells. However, both human alpha CGRP-(8-37) and human beta CGRP-(8-37) were weakly effective in antagonizing human alpha CGRP-stimulated responses in guinea-pig atria and rat vas deferens. In rat vas deferens, but not guinea-pig atria, the effects of human alpha CGRP and human alpha CGRP-(8-37) (but not human beta CGRP-(8-37)) were potentiated by thiorphan. Neither human alpha- nor human beta CGRP-(8-37) showed selectivity for supposedly CGRP1 and CGRP2 receptor-mediated responses. Furthermore, differences in the effects of the truncated CGRP analogues may reflect differences in enzyme distribution rather than the existence of CGRP receptor subtypes.
Longmore
J
J
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Hogg
J E
JE
Hutson
P H
PH
Hill
R G
RG
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D007456:Iodine Isotopes; D008297:Male; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000145:classification* / Q000378:metabolism; D015244:Thiorphan / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects
D007456:Iodine Isotopes; D010446:Peptide Fragments; D018015:Receptors, Calcitonin Gene-Related Peptide; C058636:calcitonin gene-related peptide (8-37); D015244:Thiorphan; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D015740:Calcitonin Gene-Related Peptide