TWIK1, a unique background channel with variable ion selectivity

Abstract

TWIK1 belongs to the family of background K + channels with two pore domains. In native and transfected cells, TWIK1 is detected mainly in recycling endosomes. In principal cells in the kidney, TWIK1 gene inactivation leads to the loss of a nonselective cationic conductance, an unexpected effect that was attributed to adaptive regulation of other channels. Here, we show that TWIK1 ion selectivity is modulated by extracellular pH. Although TWIK1 is K + selective at neutral pH, it becomes permeable to Na + at the acidic pH found in endosomes. Selectivity recovery is slow after restoration of a neutral pH. Such hysteresis makes plausible a role of TWIK1 as a background channel in which selectivity and resulting inhibitory or excitatory influences on cell excitability rely on its recycling rate between internal acidic stores and the plasma membrane. TWIK1−/− pancreatic β cells are more polarized than control cells, confirming a depolarizing role of TWIK1 in kidney and pancreatic cells.T wo-pore-domain potassium (K 2P ) channels constitute a unique class of background channels comprising 15 members in humans. They share the same overall architecture with four membrane-spanning segments (M1-M4), two pore domains (P1 and P2), and a large extracellular M1P1 loop. Active as dimers, they produce almost time-and voltage-independent currents that oppose membrane depolarization and cell excitability. K 2P channels have been involved in physiological functions as diverse as cellvolume regulation, apoptosis, adrenal gland development and primary hyperaldosteronism, vasodilatation, neuronal excitability and altered motor performance, central O 2 chemoreception and breathing control, perception of pain, polyunsaturated fatty acidmediated neuroprotection, and mood control. They constitute a major target of volatile anesthetics (for recent and extensive reviews on K 2P channels see refs. 1-4).Among K 2P channels, TWIK1 (also termed "K2P1" or "KCNK1") is atypical. Originally cloned from a kidney cDNA library, TWIK1 is expressed at significant levels in other tissues including heart, brain, pancreas, lung, and placenta (5-7). Upon heterologous expression, it forms homodimers (8) that produce only modest currents in Xenopus oocytes and almost no currents in cultured mammalian cells. Another hallmark is the fast inactivation of the TWIK1 currents. Because of this inactivation, their steady-state current-voltage (I-V) relationships display inward rectification, unlike the other K 2P currents that produce outwardly rectifying I-V relationships in physiological K + conditions. No native currents with similar properties have yet been reported despite the broad distribution of TWIK1. Another puzzling observation is provided by gene inactivation of TWIK1 in the mouse: Rather than a decrease of K + conductance in TWIK1−/− kidney cells, a decrease of a nonselective cationic conductance was observed that was associated with an increase in the resting membrane potential (9). More recently, it has been suggested that TWIK1 is responsible for par...

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

“…3, C-E). A most recent publication reported that the TWIK-1⅐K274E⅐I293A⅐I294A mutant (TWIK-1 surf ) channels heterologously expressed in Xenopus oocytes, which largely increase detectable TWIK-1 currents, exhibit altered ion selectivity in lowered pH o (35). However, whether TWIK-1 surf channels represent TWIK-1 wild type K ϩ channels is questionable in terms of ion selectivity because the data presented in the study showed that TWIK-1 surf channels are K ϩ -selective in pH 7.4 Na ϩ -based bath solutions with 0 and 2 mM K ϩ , not consistent with previous observations that TWIK-1 wild type channels are nonselective channels significantly permeable to extracellular Na ϩ in 0 and 2 mM [K ϩ ] o (19,32).…”

A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes

“…However, in endogenous systems, expression of TWIK-1 has been documented in various tissues, including the brain, heart and kidney 3 . Mice deficient in TWIK-1 show defects in phosphate transport in the proximal tubule and water transport in the medullary collecting duct of kidney, as well as deviations in the resting membrane potential of pancreatic b cells 4,5 . In addition, it has been recently reported that TWIK-1 conducts inward leak Na þ currents during pathological hypokalaemia in cardiomyocytes 6 .…”

Hysteresis of KcsA potassium channel's activation– deactivation gating is caused by structural changes at the channel’s selectivity filter

“…1A). Hysteresis of ion channels is linked to an ever-growing number of human physiological processes, among them normal heartbeat (2), stable rhythmic firing of pacemaking neurons, synaptic integration (3), regulation of cell excitability (4,5), and temperature sensitization of transient receptor potential channels (6,7).…”