Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic ß-cells enhances glucose-dependent insulin secretion

• Author(s) / Creator(s)

  • Chan, Catherine B.
  • Wang, Jianli
  • Sakellaropoulos, George
  • Tsushima, Robert G.
  • Joseph, Jamie W.
  • Smukler, Simon R.
  • Sewing, Sabine
  • Saleh, Monique C.
  • Wang, Jing
  • Salapatek, Anne Marie F.
  • Wheeler, Michael B.
  • MacDonald, Patrick E.

• 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.

• Date created

  2002

• Subjects / Keywords

  • Structure Function
  • Membrane Transport
  • Biogenesis

• Type of Item

  Article (Published)

• DOI

  https://doi.org/10.7939/R3JS9HN3B

• License

  © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.