Contribution of Neuronal and Glial Two-Pore-Domain Potassium Channels in Health and Neurological Disorders

Abstract

Two-pore-domain potassium (K2P) channels are widespread in the nervous system and play a critical role in maintaining membrane potential in neurons and glia. They have been implicated in many stress-relevant neurological disorders, including pain, sleep disorder, epilepsy, ischemia, and depression. K2P channels give rise to leaky K+ currents, which stabilize cellular membrane potential and regulate cellular excitability. A range of natural and chemical effectors, including temperature, pressure, pH, phospholipids, and intracellular signaling molecules, substantially modulate the activity of K2P channels. In this review, we summarize the contribution of K2P channels to neuronal excitability and to potassium homeostasis in glia. We describe recently discovered functions of K2P channels in glia, such as astrocytic passive conductance and glutamate release, microglial surveillance, and myelin generation by oligodendrocytes. We also discuss the potential role of glial K2P channels in neurological disorders. In the end, we discuss current limitations in K2P channel researches and suggest directions for future studies.

Deciphering Mechanisms of Action of Sortilin/Neurotensin Receptor-3 in the Proliferation Regulation of Colorectal and Other Cancers

“…A previous study demonstrated the interaction between the two proteins sortilin and TREK-1, in which mice with deletions of the sortilin ( sort1 ) or TREK-1 ( kcnk2 ) genes displayed a similar phenotype of resistance to depressive-like behavior during resignation tests such as the forced swimming test (FST) and the tail suspension test (TST) [ 76 ]. TREK-1 belongs to the family of two-pore-domain potassium channels, which play important roles in neuroprotectioTablen, pain, analgesia, and depression [ 77 , 78 , 79 ]. As one of the first functions identified for Sortilin/NTSR3 was to address numerous proteins from the intracellular compartments to the plasma membrane or lysosomes [ 17 , 80 ], it was crucial to determine whether sortilin and TREK-1 were associated, and if they were, how sortilin was involved in the sorting of TREK-1.…”

Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

“…Depolarisation of the resting membrane potential and neuronal hyperexcitability are consistent with previously reported data in numerous tauopathy models [ 61 , 108 , 122 , 132 ], for example in the rTg4510 mouse model, which expresses human tau variant P301L, where the pyramidal cells were depolarised by ∼8 mV compared to WT littermates [ 108 ]. The increase in input resistance and firing rate, coupled with the observed depolarisation could result from the block of a standing (or leakage) conductance for example a two-pore-domain potassium (K2P) channels that contribute to maintaining the resting potential [ 87 ]. A comparable increase in neuronal hyperexcitability has also been observed in AD patients in individuals performing memory-encoding tasks [ 28 , 41 , 56 ].…”

Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

“…Depolarisation of the resting membrane potential and neuronal hyperexcitability are consistent with previously reported data in numerous tauopathy models [59, 105, 118, 128], for example in the rTg4510 mouse model, which expresses human tau variant P301L, where the pyramidal cells were depolarised by ~8 mV compared to WT littermates [105]. The increase in input resistance and firing rate, coupled with the observed depolarisation could result from the block of a standing (or leakage) conductance for example a two-pore-domain potassium (K2P) channels that contribute to maintaining the resting potential [84].…”