Journal
JOURNAL OF GENERAL PHYSIOLOGY
Volume 120, Issue 3, Pages 307-322Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1085/jgp.20028581
Keywords
islets of Langerhans; KCa channels; ER; insulin; intracellular calcium
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Funding
- NIDDK NIH HHS [R01 DK-46409, R01 DK046409] Funding Source: Medline
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A novel calcium-dependent potassium current (K-slow) that slowly activates in response to a simulated islet burst was identified recently in mouse pancreatic beta-cells (Gopel, S.O., T Kanno, S. Barg, L. Eliasson, J. Galvanovskis, E. Renstrom, and P. Rorsman. 1999. J. Gen. Physiol. 114:759-769). K-slow activation may help terminate the cyclic bursts of Ca2+-dependent action potentials that drive Ca2+ influx and insulin secretion in beta-cells. Here, we report that when [Ca2+](i) handling was disrupted by blocking Ca2+ uptake into the ER with two separate agents reported to block the sarco/endoplasmic calcium ATPase (SERCA), thapsigargin (1-5 muM) or insulin (200 nM), K-slow was transiently potentiated and then inhibited. K-slow amplitude could also be inhibited by increasing extracellular glucose concentration from 5 to 10 mM. The biphasic modulation of K-slow by SERCA blockers could not be explained by a minimal mathematical model in which [Ca2+], is divided between two compartments, the cytosol and the ER, and K-slow activation mirrors changes in cytosolic calcium induced by the burst protocol. However, the experimental findings were reproduced by a model in which K-slow activation is mediated by a localized pool of [Ca2+] in a subspace located between the ER and the plasma membrane. In this model the subspace [Ca2+] follows changes in cytosolic [Ca2+] but with a gradient that reflects Ca2+ efflux from the ER. Slow modulation of this gradient as the ER empties and fills may enhance the role of K-slow and [Ca2+] handling in influencing beta-cell electrical activity and insulin secretion.
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