Mechanisms of inhibition of insulin release.
Sharp, Geoffrey W. G.
Department of Pharmacology, College of Veterinary Medicine, Cornell
university, Ithaca, NY 14853
APStracts 3:0195C, 1996.
Several agonists including norepinephrine, somatostatin, galanin and
prostaglandins inhibit insulin release. The inhibition is sensitive
to pertussis toxin, indicating the involvement of heterotrimeric Gi
and/or Go-proteins. Receptors for the different agonists have
different selectivity for these G proteins. After G protein
activation, the [alpha] and bg subunits dissociate and interact with
multiple targets to inhibit release. These include: 1. the KATP
channel, and perhaps other K+ channels. 2. L-type voltage dependent
Ca2+-channels. 3. adenylyl cyclase. and 4. a "distal" site
late in stimulus-secretion coupling. The latter effect, which may be
exerted close to the final stage of exocytosis, is the most powerful
of the individual inhibitory mechanisms. G-protein action on the
target molecules is determined by the individual G-proteins activated
and their specificity for the targets. The L-type Ca2+-channel is
inhibited by Go1. Adenylyl cyclase is inhibited by Gi2 and Gi3. The
distal inhibition can be exerted by Gi1, Gi2, Gi3, and Go2. Thus,
there is both selectivity and promiscuity in G-protein action in the
[beta]-cell. These characteristics allow an inhibitory ligand to be
effective at multiple targets and to act differentially from other
inhibitory ligands.
Received 21 May 1996; accepted in final form 11 June 1996.
APS Manuscript Number C327-6.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 4 July 96