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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in Pancreatic ß-Cells

Departments of Medicine and Physiology (W.E.-K., J.M.F., A.B., X.G., Y.Z., R.G.T., M.B.W.), University of Toronto, Toronto, Ontario, Canada M5S 1A8; Department of Pharmacology (P.E.M.), University of Alberta, Edmonton, Alberta, Canada T6G 2E1; Department of Medicine (T.X., R.A.L.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Institut fur Pharmakologie und Toxikologie (J.S.), Technischen Universitat Munchen, 80802 Munich, Germany

Address all correspondence and requests for reprints to: Michael B. Wheeler, Department of Physiology, 1 King’s College Circle, University of Toronto, Toronto, Canada M5S 1A8. E-mail: michael.wheeler{at}utoronto.ca; or Robert G. Tsushima, Department of Medicine, 1 King’s College Circle, University of Toronto, Toronto, Canada M5S 1A8. E-mail: r.tsushima{at}utoronto.ca.

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels mediate the pacemaker current (I_h or I_f) observed in electrically rhythmic cardiac and neuronal cells. Here we describe a hyperpolarization-activated time-dependent cationic current, ß-I_h, in pancreatic ß-cells. Transcripts for HCN1–4 were detected by RT-PCR and quantitative PCR in rat islets and MIN6 mouse insulinoma cells. ß-I_h in rat ß-cells and MIN6 cells displayed biophysical and pharmacological properties similar to those of HCN currents in cardiac and neuronal cells. Stimulation of cAMP production with forskolin/3-isobutyl-1-methylxanthine (50 µM) or dibutyryl-cAMP (1 mM) caused a significant rightward shift in the midpoint activation potential of ß-I_h, whereas expression of either specific small interfering (si)RNA against HCN2 (siHCN2b) or a dominant-negative HCN channel (HCN1-AAA) caused a near-complete inhibition of time-dependent ß-I_h. However, expression of siHCN2b in MIN6 cells had no affect on glucose-stimulated insulin secretion under normal or cAMP-stimulated conditions. Blocking ß-I_h in intact rat islets also did not affect membrane potential behavior at basal glucose concentrations. Taken together, our experiments provide the first evidence for functional expression of HCN channels in the pancreatic ß-cell.

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