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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-09-0068v1 JOE-09-0068v2 203/1/45    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zhang, Y. Articles by Wheeler, M. B PubMed PubMed Citation Articles by Zhang, Y. Articles by Wheeler, M. B

¹ Departments of Physiology and Medicine, University of Toronto, Room 7310, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
² Department of Pharmacology, Columbia University, New York, New York 10032, USA
³ Division 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
⁴ Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow CM19 5AW, UK

(Correspondence should be addressed to Y Zhang; Email: zany.zhang{at}utoronto.ca; Q Wang; Email: qinghua.wang{at}utoronto.ca)

^* (Y Zhang and Y Liu contributed equally to this work)

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 (I_h), whereas expression of dominant-negative HCN2 (HCN2-AYA) completely suppressed endogenous I_h. Compared to control β-cells, over-expression of I_h increased insulin secretion at 2.8 mmol/l glucose. However, suppression of I_h 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 (R_in), 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 R_in, 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 I_h resulted in increased membrane hyperpolarization and decreased insulin secretion. We conclude that I_h in β-cells possess the potential to modulate β-cell membrane potential and insulin secretion under hypokalemic conditions.