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.