Disease relevance of Kcnk2

• Trek1-/- mice display an increased sensitivity to ischemia and epilepsy [1].
• This region also encompasses the proton sensor E306 that is required for activation of TREK-1 by cytosolic acidosis [2].
• The TREK-1 channel protein was immunodetected in both nerve fibers and nerve cell bodies in the vestibular ganglion, both afferent fibers and nerve calyces innervating type I hair cells in the utricle and cristae [3].

High impact information on Kcnk2

• TREK-1 knockout mice have impaired PUFA-mediated neuroprotection to ischemia, reduced sensitivity to volatile anesthetics and altered perception of pain [4].
• Inhibition of TREK-1/AKAP150 by Gq-coupled receptors such as serotonin 5HT2bR and glutamate mGluR5 is much reduced when compared to TREK-1 alone [4].
• TREK-1 is highly expressed in small sensory neurons, is present in both peptidergic and nonpeptidergic neurons and is extensively colocalized with TRPV1, the capsaicin-activated nonselective ion channel [5].
• Inhibition of the TREK-1/AKAP150 complex by Gs-coupled receptors such as serotonin 5HT4sR and noradrenaline beta2AR is as extensive as for TREK-1 alone, but is faster [4].
• Protonation of E306 drastically tightens channel-phospholipid interaction and leads to TREK-1 opening at atmospheric pressure [2].

Biological context of Kcnk2

• Its amino acid sequence shares 25% identity with mouse TWIK-1, 22% with mouse TREK-1, and 33% with a putative K+ channel of Caenorhabditis elegans (C40C9) [6].
• TREK-1 emerges as a potential innovative target for developing new therapeutic agents for neurology and anesthesiology [1].
• TREK-1 may subserve some neuroprotective function in afferent nerve fibers as well as play a role in endolymph potassium homeostasis [3].
• The inactivation of the TREK-1 but not the TRAAK channel in mice results in a depression-resistant phenotype [7].
• Prostaglandin E2 and cAMP, which are strong sensitizers of peripheral and central thermoreceptors, reverse the thermal opening of TREK-1 via protein kinase A-mediated phosphorylation of Ser333 [8].

Anatomical context of Kcnk2

• TREK-1 is a two-pore-domain background potassium channel expressed throughout the central nervous system [1].
• Unlike TWIK-1, TREK-1 and TASK which are widely distributed in many different mouse tissues, TRAAK is present exclusively in brain, spinal cord and retina [9].
• TREK-1 encodes a component of the stretch-activated K(+) conductance in smooth muscles and may contribute to nitrergic inhibition of gastrointestinal muscles [10].
• Whole cell currents from TREK-1 expressed in mammalian COS cells were activated by stretch, and single channel recordings showed that the stretch-dependent conductance was due to 90 pS channels [10].
• Conversely, the actin cytoskeleton tonically represses TREK-1 mechano-sensitivity [11].

Associations of Kcnk2 with chemical compounds

• Our data suggest that the opening of background K(+) channels, like TREK-1 and TRAAK, which are activated by arachidonic acid and other polyunsaturated fatty acids such as docosahexaenoic acid and linolenic acid, is a significant factor in this neuroprotective effect [12].
• We demonstrate that the conversion of a specific glutamate residue (E306) to an alanine in this region locks TREK-1 in the open configuration and abolishes the cAMP/PKA down-modulation [13].
• Sodium nitroprusside (10(-6) or 10(-5) m) and 8-Br-cGMP (10(-4) or 10(-3) m) increased TREK-1 currents in perforated whole cell and single channel recordings [10].
• Riluzole (500 microM), selective for TREK-1 and -2 channels, enhanced acid taste responses [14].
• In contrast, halothane (< or = approximately 17 mM), which acts on TREK-1 and TASK-1 channels, blocked acid taste responses [14].
• In mice, the deletion of its gene (Kcnk2, also called TREK-1) led to animals with an increased efficacy of 5-HT neurotransmission and a resistance to depression in five different models and a substantially reduced elevation of corticosterone levels under stress [15].
• Iontophoretic delivery of acetylcholine and bradykinin in the skin of TREK1+/+ and TREK1-/- mice also shows the important role of TREK1 in cutaneous endothelium-dependent vasodilation [16].

Regulatory relationships of Kcnk2

• Here, we show that the expression of TREK-1 markedly alters the cytoskeletal network and induces the formation of actin- and ezrin-rich membrane protrusions [11].

Analytical, diagnostic and therapeutic context of Kcnk2

• TREK-1, a K+ channel involved in neuroprotection and general anesthesia [1].
• We examined their expression in mouse vallate and foliate taste buds using RT-PCR, and detected TWIK-1 and -2, TREK-1 and -2, and TASK-1 [14].
• Here, in rat ventricular cardiomyocytes using the whole-cell patch-clamp technique, we characterize for the first time a native TREK-1-like current (I(TREK)) that is activated by ATP, a purine agonist applied at a micromolar range [17].

References