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Departments of
1 Physiology
2 Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada S7N 5E5
3 Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada P7B 5E1
H2S is an important gasotransmitter, generated in mammalian cells from L-cysteine metabolism. As it stimulates KATP channels in vascular smooth muscle cells, H2S may also function as an endogenous opener of KATP channels in INS-1E cells, an insulin-secreting cell line. In the present study, KATP channel currents in INS-1E cells were recorded using the whole-cell and single-channel recording configurations of the patch-clamp technique. KATP channels in INS-1E cells have a single-channel conductance of 78 pS. These channels were activated by diazoxide and inhibited by gliclazide. ATP (3 mM) in the pipette solution inhibited KATP channels in INS-1E cells. Significant amount of H2S was produced from INS-1E cells in which the expression of cystathinonie gamma-lyase (CSE) was confirmed. After INS-1E cells were transfected with CSE-targeted short interfering RNA (CSE-siRNA) or treated with DL-propargylglycine (PPG; 1–5 mM) to inhibit CSE, endogenous production of H2S was abolished. Increase in extracellular glucose concentration significantly decreased endogenous production of H2S in INS-1E cells, and increased insulin secretion. After transfection of INS-1E cells with adenovirus containing the CSE gene (Ad-CSE) to overexpress CSE, high glucose-stimulated insulin secretion was virtually abolished. Basal KATP channel currents were significantly reduced after incubating INS-1E cells with a high glucose concentration (16 mM) or lowering endogenous H2S level by CSE-siRNA transfection. Under these conditions, exogenously applied H2S significantly increased whole-cell KATP channel currents at concentrations equal to or lower than 100 µM. H2S (100 µM) markedly increased open probability by more than 2-fold of single KATP channels (inside-out recording) in native INS-1E cells (n= 4, P < 0.05). Single-channel conductance and ATP sensitivity of KATP channels were not changed by H2S. In conclusion, endogenous H2S production from INS-1E cells varies with in vivo conditions, which significantly affects insulin secretion from INS-1E cells. H2S stimulates KATP channels in INS-1E cells, independent of activation of cytosolic second messengers, which may underlie H2S-inhibited insulin secretion from these cells. Interaction among H2S, glucose and the KATP channel may constitute an important and novel mechanism for the fine control of insulin secretion from pancreatic ß-cells.
(Received 28 August 2005;
accepted after revision 21 September 2005;
first published online 22 September 2005)
Corresponding author R. Wang: Office of Vice President (Research), Lakehead University, 955 Oliver Road, Thunder Bay, Ontario, Canada P7B 5E1. Email: rwang{at}lakeheadu.ca
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