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

G Tang, L Zhang, G Yang, L Wu, R Wang
Diabetologia 2013, 56 (3): 533-41

AIMS/HYPOTHESIS: L-type voltage-dependent Ca(2+) channels (VDCCs) in pancreatic beta cells play a critical role in regulating insulin secretion. The gasotransmitter H(2)S 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 H(2)S affects VDCCs in beta cells is unknown.

METHODS: 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 H(2)S production in pancreas were measured.

RESULTS: The H(2)S 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 H(2)S 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.

CONCLUSIONS/INTERPRETATION: Exogenous and endogenous H(2)S inhibit L-type VDCC activity and pancreatic insulin secretion, constituting a novel mechanism for the regulation of insulin secretion by the CSE/H(2)S system.

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