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Volume 271, Number 50, Issue of December 13, 1996 pp. 32241-32246
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Expression and Function of Pancreatic -Cell Delayed Rectifier K⁺ Channels
ROLE IN STIMULUS-SECRETION COUPLING

(Received for publication, September 16, 1996)

Michael Wm. Roe ^¶ , Jennings F. Worley III , Anshu A. Mittal ^¶ , Andrey Kuznetsov ^¶ , Sarmila DasGupta ^¶ , Robert J. Mertz , Sam M. Witherspoon III , Nathaniel Blair ^¶ , Mary E. Lancaster , Margaret S. McIntyre , W. Ronald Shehee , Iain D. Dukes and Louis H. Philipson ^¶

From the ^¶ Department of Medicine, University of Chicago, Chicago, Illinois 60637 and the  Glaxo Wellcome Research Institute, Research Triangle Park, North Carolina 27709

Voltage-dependent delayed rectifier K⁺ channels regulate aspects of both stimulus-secretion and excitation-contraction coupling, but assigning specific roles to these channels has proved problematic. Using transgenically derived insulinoma cells (TC3-neo) and -cells purified from rodent pancreatic islets of Langerhans, we studied the expression and role of delayed rectifiers in glucose-stimulated insulin secretion. Using reverse-transcription polymerase chain reaction methods to amplify all known candidate delayed rectifier transcripts, the expression of the K⁺ channel gene Kv2.1 in TC3-neo insulinoma cells and purified rodent pancreatic -cells was detected and confirmed by immunoblotting in the insulinoma cells. TC3-neo cells were also found to express a related K⁺ channel, Kv3.2. Whole-cell patch clamp demonstrated the presence of delayed rectifier K⁺ currents inhibited by tetraethylammonium (TEA) and 4-aminopyridine, with similar K_d values to that of Kv2.1, correlating delayed rectifier gene expression with the K⁺ currents. The effect of these blockers on intracellular Ca²⁺ concentration ([Ca²⁺]_i) was studied with fura-2 microspectrofluorimetry and imaging techniques. In the absence of glucose, exposure to TEA (1-20 mM) had minimal effects on TC3-neo or rodent islet [Ca²⁺]_i, but in the presence of glucose, TEA activated large amplitude [Ca²⁺]_i oscillations. In the insulinoma cells the TEA-induced [Ca²⁺]_i oscillations were driven by synchronous oscillations in membrane potential, resulting in a 4-fold potentiation of insulin secretion. Activation of specific delayed rectifier K⁺ channels can therefore suppress stimulus-secretion coupling by damping oscillations in membrane potential and [Ca²⁺]_i and thereby regulate secretion. These studies implicate previously uncharacterized -cell delayed rectifier K⁺ channels in the regulation of membrane repolarization, [Ca²⁺]_i, and insulin secretion.

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