TASK-2 K2P K+ channel: thoughts about gating and its fitness to physiological function

Abstract

TASK-2 (K2P5) was one of the earliest members of the K2P two-pore, four transmembrane domain K(+) channels to be identified. TASK-2 gating is controlled by changes in both extra- and intracellular pH through separate sensors: arginine 224 and lysine 245, located at the extra- and intracellular ends of transmembrane domain 4. TASK-2 is inhibited by a direct effect of CO2 and is regulated by and interacts with G protein subunits. TASK-2 takes part in regulatory adjustments and is a mediator in the chemoreception process in neurons of the retrotrapezoid nucleus where its pHi sensitivity could be important in regulating excitability and therefore signalling of the O2/CO2 status. Extracellular pH increases brought about by HCO3 (-) efflux from proximal tubule epithelial cells have been proposed to couple to TASK-2 activation to maintain electrochemical gradients favourable to HCO3 (-) reabsorption. We demonstrate that, as suspected previously, TASK-2 is expressed at the basolateral membrane of the same proximal tubule cells that express apical membrane Na(+)-H(+)-exchanger NHE-3 and basolateral membrane Na(+)-HCO3 (-) cotransporter NBCe1-A, the main components of the HCO3 (-) transport machinery. We also discuss critically the mechanism by which TASK-2 is modulated and impacts the process of HCO3 (-) reclaim by the proximal tubule epithelium, concluding that more than a mere shift in extracellular pH is probably involved.

Phosphatidylinositol (4,5)-bisphosphate dynamically regulates the K2P background K+ channel TASK-2

“…The K 2P K + channel known as TASK-2 (also K 2P 5.1)2425 is involved in bicarbonate reabsorption in the proximal tubules of the kidney26, the central detection of CO 2 and O 2 by chemo-sensitive neurons implicated in breathing control272829, and in the hearing function through an essential role in outer sulcus cells possibly in K + recycling30. From a pathophysiological point of view, TASK-2 has been implicated in a predisposition to Balkan endemic nephropathy31 through a dominant negative missense mutation supressing function3233, in the pathogenesis of multiple sclerosis and rheumatoid arthritis in humans34, and in murine inflammatory bowel disease35.…”

“…Our results show that TASK-2 is strongly phosphoinositide-dependent and that this dependence probably involves an interaction of C-terminal positively charged residues with PI(4,5)P 2 . TASK-2 is a major player in a variety of physiological processes2425 in which the phosphoinositide-dependence we have now uncovered might play a role. Our finding also points to the idea that K 2P channels, though departing in structure and regulation from other members of the K + channel superfamily, do nevertheless share some of their regulatory characteristics.…”

Gating, Regulation, and Structure in K2P K+ Channels: In Varietate Concordia?

“…TASK-2 is a K 2P channel that plays important physiologic roles (López-Cayuqueo et al, 2015), including cell volume regulation (Niemeyer et al, 2001;Barriere et al, 2003), renal bicarbonate reabsorption in the proximal tubules of the kidney (Warth et al, 2004), the central detection of CO 2 and O 2 by chemosensitive neurons implicated in breathing control (Gestreau et al, 2010;Wang et al, 2013), and in the hearing function through an essential role in cochlear outer sulcus cells possibly in K 1 recycling (Cazals et al, 2015). Certain patients with a predisposition to Balkan endemic nephropathy carry the T108P mutation in TASK-2 (Toncheva et al, 2014); TASK-2 mutant T108P does not generate any significant currents in heterologous expression experiments, and this lack of activity is consistent with a role in Balkan endemic nephropathy (Veale and Mathie, 2016).…”

14‐3‐3 Proteins regulate K2P5.1 surface expression on T lymphocytes

“…Generally, many potassium channels possess a long C‐terminal chain that contains different binding sites and consensus motifs for the interaction with intracellular signaling pathways or for the regulation of channel activity. For instance, recent studies show that G βγ subunits of heterotrimeric G proteins bind to K 2P 5.1 channels at a particular site of the C‐terminus (K257/K258) regulating their activity . Hence, using a proteomic approach, we have identified different proteins that might interact with K 2P 5.1 channels.…”

“…For instance, recent studies show that G βγ subunits of heterotrimeric G proteins bind to K 2P 5.1 channels at a particular site of the C-terminus (K257/K258) regulating their activity. 19,20 Hence, using a proteomic approach, we have identified different proteins that might interact with K 2P 5.1 channels. One of these potential interacting proteins is 14-3-3, an adaptor protein highly conserved in eukaryotic cells and ubiquitously expressed.…”