Delayed-rectifier (KV2.1) regulation of pancreatic β-cell calcium responses to glucose: inhibitor specificity and modeling

American Journal of Physiology - Endocrinology and Metabolism - Tập 289 Số 4 - Trang E578-E585 - 2005
Natalia A. Tamarina1, Andrey V. Kuznetsov2, Leonid E. Fridlyand2, Louis H. Philipson2
1Department of Medicine, University of Chicago, IL 60637, USA
2Department of Medicine, University of Chicago, Chicago, Illinois

Tóm tắt

The delayed-rectifier (voltage-activated) K+conductance (KV) in pancreatic islet β-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 KV2.1 channel protein in mouse and human islets of Langerhans. We then probed the function of KV2.1 channels in islet glucose responses by comparing the effect of hanatoxin (HaTx), a specific blocker of KV2.1 channels, with a nonspecific K+channel blocker, tetraethylammonium (TEA). Application of HaTx (1 μM) blocked delayed-rectifier currents in mouse β-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 KV2.1 channels form the predominant part of this current in the physiologically relevant range. We then employed HaTx to study the role of KV2.1 in the β-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+]ifollowed 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 β-cells. The results can be explained by a specific HaTx effect on the KVcurrent, whereas TEA affects multiple K+conductances. The results underscore the importance of KV2.1 channel in repolarization of the pancreatic β-cell plasma membrane and its role in regulating insulin secretion.

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American Journal of Physiology - Endocrinology and Metabolism

Tập 289 Số 4

E578-E585

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