Biophysical, pharmacological, and functional characteristics of cloned and native mammalian two-pore domain K+ channels

Abstract

The mammalian family of two-pore domain K+ (K2P) channel proteins are encoded by 15 KCNK genes and subdivided into six subfamilies on the basis of sequence similarities: TWIK, TREK, TASK, TALK, THIK, and TRESK. K2P channels are expressed in cells throughout the body and have been implicated in diverse cellular functions including maintenance of the resting potential and regulation of excitability, sensory transduction, ion transport, and cell volume regulation, as well as metabolic regulation and apoptosis. In recent years K2P channel isoforms have been identified as important targets of several widely employed drugs, including: general anesthetics, local anesthetics, neuroprotectants, and anti-depressants. An important goal of future studies will be to identify the basis of drug actions and channel isoform selectivity. This goal will be facilitated by characterization of native K2P channel isoforms, their pharmacological properties and tissue-specific expression patterns. To this end the present review examines the biophysical, pharmacological, and functional characteristics of cloned mammalian K2P channels and compares this information with the limited data available for native K2P channels in order to determine criteria which may be useful in identifying ionic currents mediated by native channel isoforms and investigating their pharmacological and functional characteristics.

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

“…The inward current induced by fluoxetine may be attributable to the inhibition of the low K2P basal activity, but also to the inhibition of delayed rectifier channels, that could be not completely blocked by our blockers solution, as previously reported (Hahn et al, 1999;Yeung et al, 1999). In general, quinine and quinidine are considered as K2P blockers (Lotshaw, 2007;Mathie and Veale, 2007), and in mSCG neurons, quinine (300 M) induced an inward current at Ϫ30 mV (Ϫ77.5 Ϯ 10.6 pA; n ϭ 8) that we attributed to the reduction of remaining M-current incompletely blocked by the blockers solution. Indeed, M-current inhibition by quinine has been reported in bullfrog sympathetic neurons (Imai et al, 1999) as well as in neuroblastoma cells (Robbins et al, 1992).…”

“…There are no completely specific or selective modulators distinguishing among the different K2P channel subtypes (for review, see Lotshaw, 2007), and therefore, we tested several of the innumerable pharmacological agents that interact with them. While some enabled us to rule out the participation of a given subfamily or subtype with a degree of confidence, others strongly indicated that the TREK subfamily was the origin of the riluzoleactivated outward current.…”

“…Since their discovery , the biophysical, pharmacological, and putative functional properties of cloned and heterologously expressed mammalian K2P channels have been methodically investigated. Such an effort strongly contrasts with the scarce data available from native K2P channels naturally expressed in mammalian cells (for review, see Lotshaw, 2007). Among these K2P channels, the TREK subfamily [TREK-1, TREK-2, and TWIK-related arachidonic acid-activated K ϩ channel (TRAAK)] is considered to provide a source of background potassium channels with very weak voltage dependency and a low open probability.…”

Acid-sensitive TWIK and TASK Two-pore Domain Potassium Channels Change Ion Selectivity and Become Permeable to Sodium in Extracellular Acidification

“…Two-pore domain K ϩ channels (K2P) 2 comprise the newest subfamily of K ϩ channels. Unlike other K ϩ channels that are tetramers, K2P channels are dimers with each subunit containing four transmembrane segments and two pore-forming loops (P-loop) (see Fig.…”

Physiologie, pharmacologie et modélisation de canaux potassiques

“…L'influence des canaux K + sur l'excitabilité membranaire est primordiale et vient du fait que la modulation de nombre d'entre eux et une boucle P (Figure 3), à l'origine notamment des courants K + dits à rectification entrante, ses principaux représentants étant les canaux Kir et le canal bactérien KcsA ; enfin, (3) celle des sousunités de canaux à quatre DTM (M1-M4) et deux boucles P (Figure 3) appelés canaux 2P, générant des courants qui remplissent la plupart des critères de définition d'un courant de fond ou de fuite. Les canaux 2P s'assemblent en dimères et non en tétramères pour former les canaux TWIK, THIK, TREK, TASK, TALK et TRESK [9,10].…”