Role Of K2P Channels Research Articles

The role of K₂p channels in anaesthesia and sleep.

Tandem two-pore potassium channels (K2Ps) have widespread expression in the central nervous system and periphery where they contribute to background membrane conductance. Some general anaesthetics promote the opening of some of these channels, enhancing potassium currents and thus producing a reduction in neuronal excitability that contributes to the transition to unconsciousness. Similarly, these channels may be recruited during the normal sleep-wake cycle as downstream effectors of wake-promoting neurotransmitters such as noradrenaline, histamine and acetylcholine. These transmitters promote K2P channel closure and thus an increase in neuronal excitability. Our understanding of the roles of these channels in sleep and anaesthesia has been largely informed by the study of mouse K2P knockout lines and what is currently predicted by in vitro electrophysiology and channel structure and gating.

Role of K₂p channels in stimulus-secretion coupling.

Two-pore domain K(+) (K2P) channels are involved in a variety of physiological processes by virtue of their high basal activity and sensitivity to various biological stimuli. One of these processes is secretion of hormones and transmitters in response to stimuli such as hypoxia, acidosis, and receptor agonists. The rise in intracellular [Ca(2+)] ([Ca(2+)]i) that is critical for the secretory event can be achieved by several mechanisms: (a) inhibition of resting (background) K(+) channels, (b) activation of Na(+)/Ca(2+)-permeable channels, and (c) release of Ca(2+) from intracellular stores. Here, we discuss the role of TASK and TREK in stimulus-secretion mechanisms in carotid body chemoreceptor cells and adrenal medullary/cortical cells. Studies show that stimuli such as hypoxia and acidosis cause cell depolarization and transmitter/hormone secretion by inhibition of TASK or TREK. Subsequent elevation of [Ca(2+)]i produced by opening of voltage-dependent Ca(2+) channels then activates a Na(+)-permeable cation channel, presumably to help sustain the depolarization and [Ca(2+)]i. Agonists such as angiotensin II may elevate [Ca(2+)]i via multiple mechanisms involving both inhibition of TASK/TREK and Ca(2+) release from internal stores to cause aldosterone secretion. Thus, inhibition of resting (background) K(+) channels and subsequent activation of voltage-gated Ca(2+) channels and Na(+)-permeable non-selective cation channels may be a common ionic mechanism that lead to hormone and transmitter secretion.

A Novel Mechanism of Voltage Sensing and Gating in K2P Potassium Channels

Two-pore domain (K2P) potassium channels are important regulators of cellular electrical excitability integrating a wide range of stimuli including phosphorylation, various lipids, temperature, intracellular/extracellular pH and membrane voltage. Here we investigated the mechanism of voltage sensing/gating in K2P channels. We show that TASK-3 and TRAAK are mostly closed at the resting membrane potential but become strongly activated by depolarisation similar to classical Kv channels. Moreover, strong voltage activation was also seen for other K2P channels such as TREK-1, TREK-2, TRESK and TALK-2, however, only when intracellular K+ was replaced by other permeant ions such as NH4+, Cs+ or Rb+. Strikingly, voltage activation was abolished upon intracellular Na+ or NMDG+ replacement suggesting that movements of permeant ions in the electric field focused in the selectivity filter power voltage gating and, thus, are likely to represent the gating charge in K2P channels. Indeed, mutations in the selectivity filter, experiments with high affinity pore blockers and cysteine modification establish the selectivity filter as the voltage gate. Furthermore, voltage activation in K2P channels exhibits distinct functional features compared to classical Kv channel gating as the V1/2 for voltage activation was strictly coupled to the K2P channel reversal potential and the kinetics of voltage gating were largely voltage-independent. The latter finding suggests a voltage-dependent fast multi ion binding step to a nonconductive but ion accessible selectivity filter and a second slower voltage-independent gating step leading to the conductive state of the selectivity filter. These findings demonstrate a novel concept of voltage sensing in K+ channels and point to a new role of K2P channels in cell excitability as the strong voltage dependence would enable K2P channel to contribute significantly to the repolarisation phase of neural (e.g. TRAAK) or cardiac (e.g. TASK-3) actions potentials.

New targets of inhalational anesthetics-two-pore-domain potassium channels

Background The molecular mechanism of inhalational anesthetics is not fully understood, though it had been administrated clinically for a long time. Two -pore -domain potassium channels (K2P channels), a new member of K + channels superfamily, are deemed as molecular basis of inhalational anesthetics- sensitive K+ channels. Objective To elucidate the advance in inhalational anesthetics mechanism of K2P channels via summarizing the documents related to K2P channels. Content This review concisely outlines the structure, function and classification of K2P channels and thoroughly presents the experimental evidence that inhalational anesthetics-sensitive K+ channels are the target of inhalational anesthetics. Trend To further verify the role of K2P channels in general anesthesia of inhalational anesthetics would be helpful to expound the molecular mechanism of inhalational anesthetics and develop new anesthetic drugs acting on K2P channels. Key words: Anesthetics, Inhalation; K2P channels; Targets of action

The Two-Pore-Domain Potassium Channels, TASK-1 and TASK-3, regulate Pancreatic Beta-Cell Membrane Potential in Response to pH and Anesthetics

Glucose stimulation of the pancreatic β-cell depolarizes the membrane potential to allow activation of voltage dependent calcium channels resulting in action potential (AP) firing, calcium influx, and insulin secretion. Two-pore-domain potassium (K2P) channels regulate the membrane potential from where AP firing occurs in many neurons. However, a role of K2P channels in regulating the pancreatic β-cell membrane potential is unknown and thus we addressed expression and function of the TASK K2P channels in the mouse β-cell. We find that TASK-1 and TASK-3 channels are expressed in mouse β-cells. Furthermore, β-cell TASK-like currents are sensitive to external pH, showing inhibition with acidic pH and stimulation with alkaline pH. Interestingly, glucose regulates β-cell intracellular pH causing acidic conditions in low glucose and alkaline conditions in high glucose, which may serve to regulate β-cell TASK channel activity. Increasing glucose from 2 to 14 mM caused polarization of the β-cell membrane potential whereas reducing glucose from 14 to 2 mM caused membrane depolarization by 6.1 +/- 2.2 mV when KATP was inhibited with tolbutamide. Similarly extracellular alkalinization (pH 8) resulted in polarization of the β-cell membrane potential by 9.19 +/-2.0 mV, whereas extracellular acidification (pH 6) caused membrane depolarization by 9.84 +/-2.9 mV. Anesthetic compounds that activate (halothane) or inhibit (lidocaine) TASK channels were evaluated for their ability to regulate β-cell membrane potential. Treatment of islets with lidocaine depolarized the β-cell membrane potential by 6.2 +/- 1.5 mV and halothane treatment resulted in β-cell membrane polarization. Both lidocaine and halothane have been shown to cause perturbations in human glucose homeostasis. Thus, this data implicate important roles for TASK channels in regulating the β-cell membrane potential, which may influence anesthetic and pH/glucose induced modulation of insulin secretion.

Understanding the cardiac role of K2P channels: A new TASK for electrophysiologists

See article by Putzke et al. [6] (pages 59–68) in this issue. Two-pore-domain K+ channels (K2P channels) form a newly identified class of 15 K+ channels that possess four transmembrane-spanning domains and two pore domains. Studies in heterologous systems suggest that functional K2P channels are dimers with an overall topology close to that of inward rectifier channels. Heterologous expression of these channels gives rise to instantaneous, non-inactivating K+ currents that display little or no voltage dependence, suggesting that they might contribute to background or leak currents. These channels are sensitive to a large spectrum of physical and chemical factors such as membrane stretch, temperature, oxygen tension, pH, fatty acids, phospholipids, and anesthetics [1]. Many of them are ubiquitously expressed, suggesting that they likely subserve a variety of important physiological and pathophysiological functions. Such a hypothesis is supported by studies regarding the central nervous system. For instance, TREK-1 seems to protect neuronal cells against excessive excitability and is a target for anesthetics [2], whereas TASK-1 contributes to the … *INSERM U533, l'Institut du Thorax, Faculte de Medecine, 1 rue Gaston Veil, 44035 Nantes cedex, France. Tel.: +33 240 41 28 44; fax: +33 240 41 29 50. flavien.charpentier{at}nantes.inserm.fr