Block of K_v1.7 potassium currents increases glucose‐stimulated insulin secretion

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.

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

“…Insulin secretion terminates when the b-cell is repolarized by the opening of potassium channels including members of the voltage-and calcium-activated potassium channel families. 24,25 Thus, the amount of insulin secreted is directly coupled to the electrical spiking activity of the b-cells, and each potassium channel involved in the repolarizing phase of spike plays a regulatory role in glucose-induced insulin release.…”

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

“…Voltage-gated K + channels (Kv) are intrinsic plasma membrane proteins mediating the selective flow of K + ions down their electrochemical gradient in response to a depolarization in the transmembrane electric field [1]. The selectivity and voltage dependence of Kv channels make them central players in virtually all physiological functions, including the maintenance and modulation of neuronal [2][3][4] and muscular (both cardiac and skeletal) excitability [5][6][7], regulation of calcium signalling cascades (reviewed by Reference [8]), control of cell volume [9,10], immune response [11], hormonal secretion [12], and others.…”

“…Conk-S1 (Conkunitzin-S1; Figures 2 and 3) was the first reported member of a novel family of marine toxins characterized by the Kunitz structural fold [52]. Conk-S1 is a 60-residue marine toxin from the venom of Conus striatus that blocks Shaker [52] and mammalian Kv1 channels [12]. The crystal structure of Conk-S1 displays a Kunitz-type fold in which an NH 2 -terminal 3-10 helix, 2-stranded β-sheet, and the COOH-terminal α-helix are stabilized by 2 disulfide bridges and a network of non-covalent interactions [86].…”

“…A comprehensive selectivity profile amongst Kv1, Kv2, Kv3, Kv4, BK and EAG channels is available for Conk-S1 [12]. With such information in hand, it was possible to utilize Conk-S1 as a pharmacological tool to identify the role of Kv1.7 channels in glucose-stimulated insulin secretion (GSIS) in pancreatic β cells [12]. Conk-S1 not only was useful as a molecular tool but also was shown to enhance insulin secretion ex vivo in a glucose-dependent manner in islets of Langerhans as well as in vivo in anesthetized rats.…”

“…This systematic and elegant work was performed on Kv1.2 channels (Conk-S1, IC 50 : 3.4 ± 1.3 µM) instead of the previously described highest affinity mammalian target Kv1.7. The affinity of Conk-S1 for human Kv1.7 channels is 37 ± 5 nM (Xenopus oocytes [89]) and 439 ± 82 nM for the mouse orthologue determined in mammalian cells [12]. Interestingly, comparison of the pore sequences of Kv1.1-Kv1.6 and Shaker channels lead to the conclusion that Conk-S1's preferential toxin action against the Drosophila channel (502 ± 140 nM, Xenopus oocytes) was dominated by aromatic interactions mediated by a phenylalanine in Shaker position 425, whilst in hKv1.7, a histidine (341) is present in the equivalent position.…”