AJP - Endocrinology and Metabolism, Vol 259, Issue 6 E856-E864, Copyright © 1990 by American Physiological Society
Calmodulin and insulin secretion: use of naphthalenesulfonamide compounds
G. C. Yaney and G. W. Sharp
Department of Pharmacology, New York State College of Veterinary Medicine, Cornell University, Ithaca 14853-6401.
Studies have been performed on the involvement of calmodulin in the control
of stimulated insulin secretion. The W-compounds, which are
sulfonamide-derivative calmodulin inhibitors, were used in analogue pairs
to control for hydrophobic and nonspecific effects.
N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide HCl (W-13) inhibited
glucose-stimulated insulin secretion from rat pancreatic islets over the
concentration range appropriate for an action involving calmodulin. The
control compound N-(4-aminobutyl)-2-naphthalenesulfonamide HCl (W-12)
inhibited slightly only at higher concentrations. Similar differential
inhibition by the analogue pairs was found using W-13 and W-12 and
N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide HCl (W-7) and
N-(6-aminohexyl)-1-naphthalenesulfonamide HCl (W-5) against
depolarization-induced insulin secretion in the RINm5F clonal beta-cell
line. A sufficient explanation for the inhibition of insulin release was
found in the differential inhibition of depolarization-induced Ca2+ uptake,
which located the action of the W-compounds at the voltage-dependent Ca2+
channels. These data suggest an action of the W-compounds at a point before
elevation of intracellular Ca2+ concentration [( Ca2+]i) in
stimulus-secretion coupling. In subsequent studies, with the
voltage-dependent Ca2(+)-channel agonist BAY K 8644, which increases Ca2+
uptake and the rate of insulin secretion, it was demonstrated that the
W-compounds had no effect on the stimulation of 45Ca2+ uptake or insulin
secretion. Thus the W-compounds inhibit stimulus-secretion coupling before
the elevation of [Ca2+]i but appear to have no action subsequently. These
data cast doubt on the hypothesis that calmodulin is involved in
stimulus-secretion coupling.
