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This Article Accepted manuscript (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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y. Articles by Wheeler, M. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y. Articles by Wheeler, M.

Y Zhang, Toronto, Ontario, M5S 1A8, Canada
Y Liu, Toronto, Canada
J Qu, New York, United States
A Hardy, Toronto, Canada
N Zhang, Toronto, Canada
J Diao, Toronto, Canada
P Strijbos, Harlow, United Kingdom
R Tsushima, Toronto, Canada
R Robinson, New York, United States
H Gaisano, University of Toronto, Room 7226 Medical Science Building, Ontario, Canada
Q Wang, Toronto, Canada
M Wheeler, Physiology, University of Toronto, Toronto, Ontario, Canada

Correspondence: Yi Zhang, Email: zany.zhang{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 mmol/l 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 (2.5mmol/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.