Hydrogen sulfide-induced inhibition of L-type Ca²⁺ channels and insulin secretion in mouse pancreatic beta cells

L-type voltage-dependent Ca²⁺ channels (VDCCs) in pancreatic beta cells play a critical role in regulating insulin secretion. The gasotransmitter H₂S is mostly generated from l-cysteine in pancreatic beta cells by cystathionine γ-lyase (CSE) and has been reported to inhibit insulin release by opening ATP-sensitive K⁺ channels. However, whether and how H₂S affects VDCCs in beta cells is unknown.

The whole-cell patch-clamp technique was used to record VDCCs in beta cells from Cse (also known as Cth)-knockout (KO) and wild-type (WT) mice. Insulin secretion from pancreatic islets and endogenous H₂S production in pancreas were measured.

The H₂S donor NaHS reversibly decreased L-type VDCC current density in a concentration-dependent fashion in WT pancreatic beta cells, and the current density was further inhibited by nifedipine. Furthermore, NaHS inhibited the channel recovery from depolarisation-induced inactivation, but did not shift the current–voltage (I–V) relationship. ACS67, another H₂S donor, also inhibited L-type VDCCs in beta cells. Inhibiting CSE activity with dl-propargylglycine increased the basal L-channel activity of beta cells from WT mice, but not that of beta cells from Cse-KO mice. Beta cells from Cse-KO mice displayed higher L-type VDCC density than those from WT mice. Insulin secretion from pancreatic islets was elevated in Cse-KO mice compared with WT mice. NaHS dose-dependently inhibited glucose-stimulated insulin secretion, which was further inhibited by nifedipine. Bay K-8644 increased glucose-stimulated insulin secretion, but this was counteracted by NaHS and nifedipine.

Exogenous and endogenous H₂S inhibit L-type VDCC activity and pancreatic insulin secretion, constituting a novel mechanism for the regulation of insulin secretion by the CSE/H₂S system.