title: Hydrogen sulfide-induced inhibition of L-type Ca2+ channels and insulin secretion in mouse pancreatic beta cells.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Biology, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Tang
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Yang
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.forename: R
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D004594:Electrophysiology; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D008063:Thioctic Acid / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C546828:ACS67 compound; D020746:Calcium Channels, L-Type; D007328:Insulin; D011461:Prostaglandins F, Synthetic; D008063:Thioctic Acid; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide