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      Emerging Roles of TWIK-1 Heterodimerization in the Brain


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          Two-pore domain K + (K2P) channels play essential roles in regulating resting membrane potential and cellular excitability. Although TWIK-1 (TWIK—tandem of pore domains in a weak inward rectifying K + channel) was the first identified member of the K2P channel family, it is only in recent years that the physiological roles of TWIK-1 have been studied in depth. A series of reports suggest that TWIK-1 may underlie diverse functions, such as intrinsic excitability of neurons, astrocytic passive conductance, and astrocytic glutamate release, as a homodimer or heterodimer with other K2P isotypes. Here, we summarize expression patterns and newly identified functions of TWIK-1 in the brain.

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          Molecular background of leak K+ currents: two-pore domain potassium channels.

          Two-pore domain K(+) (K(2P)) channels give rise to leak (also called background) K(+) currents. The well-known role of background K(+) currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K(2P) channel types) that this primary hyperpolarizing action is not performed passively. The K(2P) channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K(2P) channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K(2P) channel family into the spotlight. In this review, we focus on the physiological roles of K(2P) channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.
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            TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation.

            Astrocytes release glutamate upon activation of various GPCRs to exert important roles in synaptic functions. However, the molecular mechanism of release has been controversial. Here, we report two kinetically distinct modes of nonvesicular, channel-mediated glutamate release. The fast mode requires activation of G(αi), dissociation of G(βγ), and subsequent opening of glutamate-permeable, two-pore domain potassium channel TREK-1 through direct interaction between G(βγ) and N terminus of TREK-1. The slow mode is Ca(2+) dependent and requires G(αq) activation and opening of glutamate-permeable, Ca(2+)-activated anion channel Best1. Ultrastructural analyses demonstrate that TREK-1 is preferentially localized at cell body and processes, whereas Best1 is mostly found in microdomains of astrocytes near synapses. Diffusion modeling predicts that the fast mode can target neuronal mGluR with peak glutamate concentration of 100 μM, whereas slow mode targets neuronal NMDA receptors at around 1 μM. Our results reveal two distinct sources of astrocytic glutamate that can differentially influence neighboring neurons. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Cns distribution of members of the two-pore-domain (KCNK) potassium channel family.

              Two-pore-domain potassium (K(+)) channels are substrates for resting K(+) currents in neurons. They are major targets for endogenous modulators, as well as for clinically important compounds such as volatile anesthetics. In the current study, we report on the CNS distribution in the rat and mouse of mRNA encoding seven two-pore-domain K(+) channel family members: TASK-1 (KCNK3), TASK-2 (KCNK5), TASK-3 (KCNK9), TREK-1 (KCNK2), TREK-2 (KCNK10), TRAAK (KCNK4), and TWIK-1 (KCNK1). All of these genes were expressed in dorsal root ganglia, and for all of the genes except TASK-2, there was a differential distribution in the CNS. For TASK-1, highest mRNA accumulation was seen in the cerebellum and somatic motoneurons. TASK-3 was much more widely distributed, with robust expression in all brain regions, with particularly high expression in somatic motoneurons, cerebellar granule neurons, the locus ceruleus, and raphe nuclei and in various nuclei of the hypothalamus. TREK-1 was highest in the striatum and in parts of the cortex (layer IV) and hippocampus (CA2 pyramidal neurons). mRNA for TRAAK also was highest in the cortex, whereas expression of TREK-2 was primarily restricted to the cerebellar granule cell layer. There was widespread distribution of TWIK-1, with highest levels in the cerebellar granule cell layer, thalamic reticular nucleus, and piriform cortex. The differential expression of each of these genes likely contributes to characteristic excitability properties in distinct populations of neurons, as well as to diversity in their susceptibility to modulation.

                Author and article information

                Int J Mol Sci
                Int J Mol Sci
                International Journal of Molecular Sciences
                24 December 2017
                January 2018
                : 19
                : 1
                : 51
                [1 ]School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul 136-703, Korea; chois007@ 123456korea.ac.kr
                [2 ]Korea Institute of Science and Technology (KIST), Center for Functional Connectomics, Seoul 02792, Korea
                [3 ]KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea
                Author notes
                [* ]Correspondence: emhwang@ 123456kist.re.kr (E.M.H.); jaeyong68@ 123456korea.ac.kr (J.-Y.P.); Tel.: +82-2-958-7216 (E.M.H.); +82-2-3290-5637 (J.-Y.P.); Fax: +82-2-958-7219 (E.M.H.); +82-2-921-7207 (J.-Y.P.)
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 28 November 2017
                : 22 December 2017

                Molecular biology
                Molecular biology
                twik-1, k2p, astrocyte, brain, heterodimerization


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