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Free keywords:
Conkunitzin-S1; electrical signalling; GSIS; pancreas; potassium
channels
Abstract:
Glucose-stimulated insulin secretion (GSIS) relies on repetitive, electrical spiking
activity of the beta cell membrane. Cyclic activation of voltage-gated potassium
channels (K
v
) generates an outward, ‘delayed rectifier’ potassium current, which
drives the repolarizing phase of each spike and modulates insulin release. Although
several K
v
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 K
v
1.7 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 K
v
1.7-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 K
v
1.7 contributes to the
membrane-repolarizing current of beta cells during GSIS and that block of this
specific component of beta cell K
v
current offers a potential strategy for enhancing
GSIS with minimal risk of hypoglycaemia during metabolic disorders such as
Type 2 diabetes.
