Calmodulin and insulin secretion: use of naphthalenesulfonamide compounds

Abstract

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.