Differential antagonism of amylin's metabolic and vascular actions with amylin receptor antagonists

Author:

Beaumont K.,Moore C. X.,Pittner R. A.,Prickett K. S.,Gaeta L. S. L.,Rink T. J.,Young A. A.

Abstract

High affinity amylin binding sites are present in the rat nucleus accumbens. These sites bind [125I]amylin with an affinity of 27 pM and have high affinity for salmon calcitonin (sCT) and moderately high affinity for calcitonin gene related peptide (CGRP). N-terminally truncated peptides were tested for their ability to compete for [125I]amylin binding to these sites and to antagonize the metabolic and vascular actions of amylin. CGRP(8–37), sCT(8–32), and ac-[Asn30,Tyr32]sCT(8–32) (AC187) inhibited [125I]amylin binding to rat nucleus accumbens. Order of potency at inhibiting amylin binding (AC187 > sCT(8–32) > CGRP(8–37)) differed from the order of potency at inhibiting [125I]CGRP binding to SK-N-MC neuroblastoma cells (CGRP(8–37) > AC187 > sCT(8–32)). AC187 was the most potent antagonist of amylin's effects on isolated rat soleus muscle glycogen metabolism, and it was more effective than either sCT(8–32) or CGRP(8–37) at reducing amylin-stimulated hyperlactemia in rats. In contrast, CGRP(8–37) was the most potent peptide at antagonizing amylin-induced hypotension in rats. Amylin's hypotensive actions appear to be mediated by a weak action at CGRP receptors, while its metabolic actions are mediated by receptors with a distinct antagonist profile. AC187 is a potent antagonist of amylin binding sites in nucleus accumbens and of amylin's metabolic actions.Key words: amylin, calcitonin gene related peptide, diabetes, skeletal muscle, peptide receptors.

Publisher

Canadian Science Publishing

Subject

Physiology (medical),Pharmacology,General Medicine,Physiology

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