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ARTICLE |
SK Channels Contribute to Kslow Tail Current and Modulate Insulin Secretion
2 Department of Physiology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23284
3 Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637
4 Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232
5 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232
6 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
Correspondence to L.S. Satin: lsatin{at}mail2.vcu.edu
The pharmacological properties of slow Ca2+-activated K+ current (Kslow) were investigated in mouse pancreatic ß-cells and islets to understand how Kslow contributes to the control of islet bursting, [Ca2+]i oscillations, and insulin secretion. Kslow was insensitive to apamin or the KATP channel inhibitor tolbutamide, but UCL 1684, a potent and selective nonpeptide SK channel blocker reduced the amplitude of Kslow tail current in voltage-clamped mouse ß-cells. Kslow was also selectively and reversibly inhibited by the class III antiarrythmic agent azimilide (AZ). In isolated ß-cells or islets, pharmacologic inhibition of Kslow by UCL 1684 or AZ depolarized ß-cell silent phase potential, increased action potential firing, raised [Ca2+]i, and enhanced glucose-dependent insulin secretion. AZ inhibition of Kslow also supported mediation by SK, rather than cardiac-like slow delayed rectifier channels since bath application of AZ to HEK 293 cells expressing SK3 cDNA reduced SK current. Further, AZ-sensitive Kslow current was extant in ß-cells from KCNQ1 or KCNE1 null mice lacking cardiac slow delayed rectifier currents. These results strongly support a functional role for SK channel-mediated Kslow current in ß-cells, and suggest that drugs that target SK channels may represent a new approach for increasing glucose-dependent insulin secretion. The apamin insensitivity of ß-cell SK current suggests that ß-cells express a unique SK splice variant or a novel heteromultimer consisting of different SK subunits.
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