Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

Abstract

Two-pore-domain potassium (K2P-) channels conduct outward K+ currents that maintain the resting membrane potential and modulate action potential repolarization. Members of the K2P channel family are widely expressed among different human cell types and organs where they were shown to regulate important physiological processes. Their functional activity is controlled by a broad variety of different stimuli, like pH level, temperature, and mechanical stress but also by the presence of lipids or pharmacological agents. In patients suffering from cardiovascular diseases, alterations in K2P-channel expression and function have been observed, suggesting functional significance and a potential therapeutic role of these ion channels. For example, upregulation of atrial specific K2P3.1 (TASK-1) currents in atrial fibrillation (AF) patients was shown to contribute to atrial action potential duration shortening, a key feature of AF-associated atrial electrical remodelling. Therefore, targeting K2P3.1 (TASK-1) channels might constitute an intriguing strategy for AF treatment. Further, mechanoactive K2P2.1 (TREK-1) currents have been implicated in the development of cardiac hypertrophy, cardiac fibrosis and heart failure. Cardiovascular expression of other K2P channels has been described, functional evidence in cardiac tissue however remains sparse. In the present review, expression, function, and regulation of cardiovascular K2P channels are summarized and compared among different species. Remodelling patterns, observed in disease models are discussed and compared to findings from clinical patients to assess the therapeutic potential of K2P channels.

Unraveling the Role of K2P Channels in Atrial Fibrillation

“…K 2 P channels have been considered voltageindependent ion channels, since there is no voltage-sensing domain (VSD) in their structure, where their strong outward rectification arises from the asymmetric K + gradient across the membrane following the Goldman-Hodgkin-Katz equation. K 2 P channels produce basically instantaneous and non-inactivatable currents an extensive range of the membrane potential (Vm) [24].…”

“…Due to these characteristic biophysical properties K 2 P channels are also known as background or "leak" K + channels with important implications in stabilizing Vrest and contributing to repolarization. Whereas the TASK1 currents conform to the Goldman-Hodgkin-Katz equation, other K 2 P channels may exhibit variations: i.e., TREK1 have a slight outward; TWIK1/TWIK2 channels have inward rectification; there is a slow inactivation component that represents for approximately 50% of TWIK2 cur-rent; and TRESK shows asymmetric gating behavior [24][25][26]. Interestingly a noteworthy voltage-dependent activation has been found in some K 2 P channels, nevertheless the exact mechanism remains uncertain due to the lack of a canonical voltage-sensing domain in channel structure [27].…”

“…New research in this area may improve our knowledge about K 2 P channel function. K 2 P channel family is really fascinating since several studies have demonstrated that the expression of TWIK-1, TREK-1, TASK-1, TASK-2 and TASK-3 are dysregulated in AF [6,11,23,24,[31][32][33]. Moreover, the loss of function (LoF) mutations on TASK1-enconding gene have been reported in patients with familiar AF [34].…”

“…Another study also demonstrated that the TWIK-1 channel could change its permeability to Na + by promoting membrane depolarization under conditions of hypokalemia and acidosis. The changes in TWIK-1 ion selectivity could increase excitability of atrial cardiomyocytes resulting in enhanced automaticity under these conditions predisposing to tachycardia and AF development [24]. In this case, where the selectivity of K + is replaced by Na + will be also effective TWIK-1 blockers to preventing AF.…”

Research Progress on Natural Products’ Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels

“…By starting membrane depolarization, VK allows K+ efflux and regulates cardiac action potential duration. K2P- channels conduct outward K+ currents and modulate action potential repolarization [ 16 ].…”