Upregulation of K _2P 3.1 K ⁺ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

Abstract

Background-Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanismbased approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K 2P 3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K + channel-related acid-sensitive K + channel-1]) 2-poredomain K + (K 2P ) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. Methods and Results-Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage-and current-clamp techniques. K 2P 3.1 subunits exhibited predominantly atrial expression, and atrial K 2P 3.1 transcript levels were highest among functional K 2P channels. K 2P 3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD 90 ) compared with patients in sinus rhythm. In contrast, K 2P 3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K 2P 3.1 inhibition prolonged APD 90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Conclusions-Enhancement of atrium-selective K 2P 3.1 currents contributes to APD shortening in patients with chronic AF, and K 2P 3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K 2P 3.1 as a novel drug target for mechanism-based AF therapy.

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

“…For instance, enhanced KCNK3 activity was recently demonstrated in atrial myocytes of patients with chronic atrial fibrillation, leading to shortening of the action potential duration 44. Mechanistic understanding of ONO's regulation of KCNK3 would aid the development of more selective pharmacological modulators of channel activity.…”

Letter by Olschewski et al Regarding Article, “Upregulation of K 2P 3.1 K + Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation”

“…We read with interest the article "Upregulation of K 2P 3.1 K + Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation" by Schmidt et al 1 The authors report that pharmacological inhibition of K 2P 3.1, also called TASK-1, in vitro prolongs action potential duration in cardiac myocytes obtained from patients with chronic atrial fibrillation. They suggest that lengthening action potential duration may be a novel therapeutic approach for mechanism-based atrial fibrillation therapy.…”

Stress-Kinase Regulation of TASK-1 and TASK-3

“…For instance TASK-1 channels are promising drug targets for the treatment of AFib, as they are upregulated under AFib [9, 10] and as these channels have the ability to modulate the human atrial action potential duration under normal and pathological conditions [5, 10]. As in humans TASK-1 lacks a ventricular expression [5], a pharmacological inhibition of this channel can prolong atrial refractoriness and convert AFib, without causing life threatening ventricular side effects [4, 5].…”