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Experimental and Theoretical Studies
2 Physiology, Medical College of Virginia at Virginia Commonwealth University, Richmond, VA 2398
3 Medicine (Endocrinology), Medical College of Virginia at Virginia Commonwealth University, Richmond, VA 2398
4 Department of Mathematics and Kasha Laboratory of Biophysics, Florida State University, Tallahassee, FL 32306
5 Mathematical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
Address correspondence to Leslie S. Satin, Department of Pharmacology and Toxicology, Medical College of Virginia Virginia Commonwealth University, P.O. Box 980524, Richmond, VA 23298. Fax: (804) 828-1532; E-mail: lsatin{at}hsc.vcu.edu
A novel calcium-dependent potassium current (Kslow) that slowly activates in response to a simulated islet burst was identified recently in mouse pancreatic ß-cells (Göpel, S.O., T. Kanno, S. Barg, L. Eliasson, J. Galvanovskis, E. Renström, and P. Rorsman. 1999. J. Gen. Physiol. 114:759–769). Kslow activation may help terminate the cyclic bursts of Ca2+-dependent action potentials that drive Ca2+ influx and insulin secretion in ß-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 µM) or insulin (200 nM), Kslow was transiently potentiated and then inhibited. Kslow amplitude could also be inhibited by increasing extracellular glucose concentration from 5 to 10 mM. The biphasic modulation of Kslow by SERCA blockers could not be explained by a minimal mathematical model in which [Ca2+]i is divided between two compartments, the cytosol and the ER, and Kslow activation mirrors changes in cytosolic calcium induced by the burst protocol. However, the experimental findings were reproduced by a model in which Kslow 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 Kslow and [Ca2+] handling in influencing ß-cell electrical activity and insulin secretion.
Key Words: islets of Langerhans • KCa channels • ER • insulin • intracellular calcium
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