Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic ß-cells enhances glucose-dependent insulin secretion
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MacDonald, P. E., Sewing, S., Wang, J., Joseph, J. W., Smukler, S. R., Sakellaropoulos, G., Wang, J., Saleh, M. C., Chan, C. B., Tsushima, R., Salapatek, A. M. F., & Wheeler, M. B. (2002). Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic ß-cells enhances glucose-dependent insulin secretion. Journal of Biological Chemistry, 277(47), 44938-44945. http://dx.doi.org/10.1074/jbc.M205532200
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http://dx.doi.org/10.1074/jbc.M205532200
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Voltage-dependent (Kv) outward K+ currents repolarize β-cell action potentials during a glucose stimulus to limit Ca2+ entry and insulin secretion. Dominant-negative “knockout” of Kv2 family channels enhances glucose-stimulated insulin secretion. Here we show that a putative Kv2.1 antagonist (C-1) stimulates insulin secretion from MIN6 insulinoma cells in a glucose- and dose-dependent manner while blocking voltage-dependent outward K+currents. C-1-blocked recombinant Kv2.1-mediated currents more specifically than currents mediated by Kv1, -3, and -4 family channels (Kv1.4, 3.1, 4.2). Additionally, C-1 had little effect on currents recorded from MIN6 cells expressing a dominant-negative Kv2.1 α-subunit. The insulinotropic effect of acute Kv2.1 inhibition resulted from enhanced membrane depolarization and augmented intracellular Ca2+ responses to glucose. Immunohistochemical staining of mouse pancreas sections showed that expression of Kv2.1 correlated highly with insulin-containing β-cells, consistent with the ability of C-1 to block voltage-dependent outward K+ currents in isolated mouse β-cells. Antagonism of Kv2.1 in an ex vivoperfused mouse pancreas model enhanced first- and second-phase insulin secretion, whereas glucagon secretion was unaffected. The present study demonstrates that Kv2.1 is an important component of β-cell stimulus-secretion coupling, and a compound that enhances, but does not initiate, β-cell electrical activity by acting on Kv2.1 would be a useful antidiabetic agent.
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http://purl.org/coar/resource_type/c_6501 http://purl.org/coar/version/c_970fb48d4fbd8a85
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© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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en