Inhibition of Kv2.1 Voltage-dependent K+Channels in Pancreatic β-Cells Enhances Glucose-dependent Insulin Secretion

• Published in: The Journal of biological chemistry Vol. 277; no. 47; p. 44938
• Main Authors: Patrick E. MacDonald, Sabine Sewing, Jianli Wang, Jamie W. Joseph, Simon R. Smukler, George Sakellaropoulos, Jing Wang, Monique C. Saleh, Catherine B. Chan, Robert G. Tsushima, Anne Marie F. Salapatek, Michael B. Wheeler
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 22.11.2002
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M205532200

Voltage-dependent (Kv) outward K + currents repolarize β-cell action potentials during a glucose stimulus to limit Ca 2+ 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 Ca 2+ 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 vivo perfused 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.