• Made available online as an Accepted Preprint 4 August 2009
  • Accepted Preprint first posted online on 4 August 2009

Functional characterization of hyperpolarization-activated cyclic nucleotide-gated channels in rat pancreatic β cells

  1. Michael B Wheeler1
  1. 1Departments of Physiology and Medicine, University of Toronto, Room 7310, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
    2Department of Pharmacology, Columbia University, New York, New York 10032, USA
    3Division of Endocrinology and Metabolism, Li Ka-Shing Knowledge Institute, St Michael's Hospital, Room 7005, Queen Wing, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8
    4Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow CM19 5AW, UK
  1. (Correspondence should be addressed to Y Zhang; Email: zany.zhang{at}utoronto.ca; Q Wang; Email: qinghua.wang{at}utoronto.ca)


Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate pacemaker activity in some cardiac cells and neurons. In the present study, we have identified the presence of HCN channels in pancreatic β-cells. We then examined the functional characterization of these channels in β-cells via modulating HCN channel activity genetically and pharmacologically. Voltage-clamp experiments showed that over-expression of HCN2 in rat β-cells significantly increased HCN current (Ih), whereas expression of dominant-negative HCN2 (HCN2-AYA) completely suppressed endogenous Ih. Compared to control β-cells, over-expression of Ih increased insulin secretion at 2.8 mmol/l glucose. However, suppression of Ih did not affect insulin secretion at both 2.8 and 11.1 mmol/l glucose. Current-clamp measurements revealed that HCN2 over-expression significantly reduced β-cell membrane input resistance (Rin), and resulted in a less-hyperpolarizing membrane response to the currents injected into the cell. Conversely, dominant negative HCN2-AYA expression led to a substantial increase of Rin, which was associated with a more hyperpolarizing membrane response to the currents injected. Remarkably, under low extracellular potassium conditions (2.5 mmol/l K+), suppression of Ih resulted in increased membrane hyperpolarization and decreased insulin secretion. We conclude that Ih in β-cells possess the potential to modulate β-cell membrane potential and insulin secretion under hypokalemic conditions.

  • Received in final form 29 July 2009
  • Accepted 4 August 2009
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