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Delayed-rectifier (K_V2.1) regulation of pancreatic -cell calcium responses to glucose: inhibitor specificity and modeling

Department of Medicine, University of Chicago, Chicago, Illinois

Submitted 8 February 2005 ; accepted in final form 5 May 2005

The delayed-rectifier (voltage-activated) K⁺ conductance (K_V) in pancreatic islet -cells has been proposed to regulate plasma membrane repolarization during responses to glucose, thereby determining bursting and Ca²⁺ oscillations. Here, we verified the expression of K_V2.1 channel protein in mouse and human islets of Langerhans. We then probed the function of K_V2.1 channels in islet glucose responses by comparing the effect of hanatoxin (HaTx), a specific blocker of K_V2.1 channels, with a nonspecific K⁺ channel blocker, tetraethylammonium (TEA). Application of HaTx (1 µM) blocked delayed-rectifier currents in mouse -cells, resulting in a 40-mV rightward shift in threshold of activation of the voltage-dependent outward current. In the presence of HaTx, there was negligible voltage-activated outward current below 0 mV, suggesting that K_V2.1 channels form the predominant part of this current in the physiologically relevant range. We then employed HaTx to study the role of K_V2.1 in the -cell Ca²⁺ responses to elevated glucose in comparison with TEA. Only HaTx was able to induce slow intracellular Ca²⁺ concentration ([Ca²⁺]_i) oscillations in cells stimulated with 20 mM glucose, whereas TEA induced an immediate rise in [Ca²⁺]_i followed by rapid oscillations. In human islets, HaTx acted in a similar fashion. The data were analyzed using a detailed mathematical model of ionic flux and Ca²⁺ regulation in -cells. The results can be explained by a specific HaTx effect on the K_V current, whereas TEA affects multiple K⁺ conductances. The results underscore the importance of K_V2.1 channel in repolarization of the pancreatic -cell plasma membrane and its role in regulating insulin secretion.

delayed-rectified potassium conductance; hanatoxin; tetraethylammonium; intracellular calcium

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