Abstract
Glucose-stimulated insulin secretion (GSIS) relies on repetitive, electrical spiking activity of the beta cell membrane. Cyclic activation of voltage-gated potassium channels (Kv) generates an outward, ‘delayed rectifier’ potassium current, which drives the repolarizing phase of each spike and modulates insulin release. Although several Kv channels are expressed in pancreatic islets, their individual contributions to GSIS remain incompletely understood. We take advantage of a naturally occurring cone-snail peptide toxin, Conkunitzin-S1 (Conk-S1), which selectively blocks Kv1.7 channels to provide an intrinsically limited, finely graded control of total beta cell delayed rectifier current and hence of GSIS. Conk-S1 increases GSIS in isolated rat islets, likely by reducing Kv1.7-mediated delayed rectifier currents in beta cells, which yields increases in action potential firing and cytoplasmic free calcium. In rats, Conk-S1 increases glucose-dependent insulin secretion without decreasing basal glucose. Thus, we conclude that Kv1.7 contributes to the membrane-repolarizing current of beta cells during GSIS and that block of this specific component of beta cell Kv current offers a potential strategy for enhancing GSIS with minimal risk of hypoglycaemia during metabolic disorders such as Type 2 diabetes.
Highlights
Increase in ATP due to glucose metabolism causes the closure of KATP channels, leading to depolarization and opening of voltage-gated calcium and (1) Faculty of Medicine, Department of Physiology and Pharmacology, and HBI, University of Calgary, Calgary, AB, Canada (2) Max-Planck-Institute for Experimental Medicine, Gottingen, Germany (3) Department of Cell Biology and Physiology, Washington UniversitySchool of Medicine, St
We conclude that Kv1.7 contributes to the membrane-repolarizing current of beta cells during Glucose-stimulated insulin secretion (GSIS) and that block of this specific component of beta cell Kv current offers a potential strategy for enhancing GSIS with minimal risk of hypoglycaemia during metabolic disorders such as Type 2 diabetes
The present work shows that Conk-S1 enhances GSIS via Kv channel modulation
Summary
Secretion terminates when the beta cell is repolarized by the opening of potassium channels including members of the voltage- (Kv) and calcium-activated (KCa) potassium channel families (Braun et al, 2008; Houamed et al, 2010; Jacobson et al, 2010). The amount of insulin secreted is directly coupled to the electrical activity of the beta cell, and modulation of the multiple ion channels involved offers different alternatives for the treatment of glucose homeostasis related disorders such as diabetes. The kinetics of the beta cell KCa currents (mediated by SK, IK and BK channels) suggest their capability to modulate various aspects of electrical bursting activity, including action potential shape and amplitude. Multiple Kv a-subunits, including Kv1.7, are expressed at high levels (Kalman et al, 1998; Smith et al, 1990), suggesting that these Kv subtypes contribute to the remainder of the beta cell delayed rectifier current. We identify Conkunitzin-S1 (Conk-S1), as a preferential peptide blocker of Kv1.7, and an experimental tool to dissect the role of Kv1.7 in the regulation of insulin secretion, as well as a possible molecular archetype for the design of new pharmacological agents to control glucose homeostasis
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