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Voltage-gated ion channels in human pancreatic β-cells Electrophysiological characterization and role in insulin secretion

¹Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK
²Nuffield Department of Surgery, John Radcliffe Hospital, Oxford OX3 9DU, UK

Objective: To characterize the voltage-gated ion channels in human β-cells from non-diabetic donors and their role in glucose-stimulated insulin release.

Research Design and Methods: Insulin release was measured from intact islets. Whole-cell patch-clamp experiments and measurements of cell capacitance were performed on isolated β-cells. The ion channel complement was determined by quantitative PCR.

Results: Human β-cells express two types of voltage-gated K⁺-currents that flow through delayed rectifying (K_V2.1/2.2) and large-conductance Ca²⁺-activated (BK) K⁺-channels. Blockade of BK-channels (using iberiotoxin) increased action potential amplitude and enhanced insulin secretion by 70% whereas inhibition of K_V2.1/2.2 (with stromatoxin) was without stimulatory effect on electrical activity and secretion. Voltage-gated TTX-sensitive Na⁺-currents (Na_V1.6/1.7) contribute to the upstroke of action potentials. Inhibition of Na⁺-currents with TTX reduced glucose-stimulated (6–20 mM) insulin secretion by 55–70%. Human β-cells are equipped with L- (Ca_V1.3), P/Q- (Ca_V2.1) and T- (Ca_V3.2), but not N- or R-type Ca²⁺-channels. Blockade of L-type channels abolished glucose-stimulated insulin release while inhibition of T- and P/Q-type Ca²⁺-channels reduced glucose-induced (6 mM) secretion by 60–70%. Membrane potential recordings suggest that L- and T-type Ca²⁺-channels participate in action potential generation. Blockade of P/Q-type Ca²⁺-channels suppressed exocytosis (measured as an increase in cell capacitance) by >80% whereas inhibition of L-type Ca²⁺-channels only had a minor effect.

Conclusions: Voltage-gated T-type and L-type Ca²⁺-channels as well as Na⁺-channels participate in glucose-stimulated electrical activity and insulin secretion. Ca²⁺-activated BK-channels are required for rapid membrane repolarisation. Exocytosis of insulin-containing granules is principally triggered by Ca²⁺ influx through P/Q- type Ca²⁺-channels.

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