Gating the pore of potassium leak channels

Abstract

A key feature of potassium channel function is the ability to switch between conducting and non-conducting states by undergoing conformational changes in response to cellular or extracellular signals. Such switching is facilitated by the mechanical coupling of gating domain movements to pore opening and closing. Two-pore domain potassium channels (K(2P)) conduct leak or background potassium-selective currents that are mostly time- and voltage-independent. These channels play a significant role in setting the cell resting membrane potential and, therefore modulate cell responsiveness and excitability. Thus, K(2P) channels are key players in numerous physiological processes and were recently shown to also be involved in human pathologies. It is well established that K(2P) channel conductance, open probability and cell surface expression are significantly modulated by various physical and chemical stimuli. However, in understanding how such signals are translated into conformational changes that open or close the channels gate, there remain more open questions than answers. A growing line of evidence suggests that the outer pore area assumes a critical role in gating K(2P) channels, in a manner reminiscent of C-type inactivation of voltage-gated potassium channels. In some K(2P) channels, this gating mechanism is facilitated in response to external pH levels. Recently, it was suggested that K(2P) channels also possess a lower activation gate that is positively coupled to the outer pore gate. The purpose of this review is to present an up-to-date summary of research describing the conformational changes and gating events that take place at the K(2P) channel ion-conducting pathway during the channel regulation.

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

“…The recent experiments of Bagriantsev et al (2011Bagriantsev et al ( , 2012, Piechotta et al (2011), and Rapedius et al (2012) suggest that TREK1 channels may not gate directly at the lower bundle-crossing like many other classic tetrameric K 1 channels (Cohen et al, 2009;Mathie et al, 2010). Instead, it appears that most if not all regulators of TREK1 activity produce their effect by altering gating at the selectivity filter of the channel, regardless of where in the channel they interact.…”

Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: Relevance to trypanosome lysis

“…For example, the pH-dependent opening of the so-called TASK-2 and Kir1.1 channels involves the respective deprotonation of an arginine (pK a = 8) and a lysine (pK a = 7) residue (34,35), which may lead to large conformational changes or local perturbations of the selectivity filter (36). Thus, it appears that APOL1 combines the pH-dependent solubility characteristics of bacterial pore-forming toxins, with the complex pH-gating behaviors more typical of eukaryotic channels.…”

An Extracellular Ion Pathway Plays a Central Role in the Cooperative Gating of a K2P K+ Channel by Extracellular pH*

“…Gating of K 2P channels by extracellular H ϩ is known to occur at the selectivity filter by a process that has been thought to be, at least superficially, akin to C-type inactivation commonly encountered in other K ϩ channels (reviewed in Ref. 34). K ϩ dependence of TASK-1 pH o gating is in accord with this concept (11,35).…”