Block of Ca2+‐channels by alpha‐endosulphine inhibits insulin release

α-Endosulphine, isolated as an endogenous equivalent for sulphonylureas, is a 121-amino acids protein of 19 kDa apparent molecular mass, member of a cyclic AMP-regulated phosphoprotein family. We have previously shown that α-endosulphine inhibits sulphonylurea binding and KATP channel activity, thereby stimulating basal insulin secretion. We now describe that in the perfused rat pancreas, no stimulation was detected and that α-endosulphine inhibited glucose stimulated insulin release. This inhibition was dose-dependent and affected both phases of insulin secretion. This inhibitory effect of α-endosulphine also occurred on MIN6 β-cells when insulin release was stimulated either by glucose, sulphonylureas or a high K+ depolarization. Inhibition was concentration-dependent with a half-maximal inhibition at 0.5 μM and was mirrored by inhibition of calcium influx. Electrophysiological experiments demonstrated, in comparison to the effects of the sulphonylurea tolbutamide, that these inhibitory effects were linked to a direct inhibition of L-type Ca2+-channels and were independent from a regulation of KATP channels. Although α-endosulphine is able to stimulate insulin release under specific conditions acting via modulation of KATP channel activity, the present study suggests that, under physiological conditions, the peptide mainly acts to block voltage-gated Ca2+-channels. This block leads to the inhibition of calcium influx and triggers inhibition of insulin release. We conclude that α-endosulphine is not exclusively an endogenous equivalent for sulphonylureas and not solely a KATP channel regulator. British Journal of Pharmacology (2002) 135, 1810–1818; doi:10.1038/sj.bjp.0704635