Emerging Roles of TWIK-1 Heterodimerization in the Brain

Cho, Chang Hoon; Hwang, Eun Mi; Park, Jae Yong

doi:10.3390/ijms19010051

Cited by 9 publications

(12 citation statements)

References 50 publications

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“…In mHb ChNs, there are high expressions of at least two types of K 2P channels, TASK-3 and TWIK-1 45 . The two K 2P channels may interact to form heteromeric channels as well as homomeric ones 58, 59 , which may exhibit unique pharmacology. Thus, low expressions of histamine receptors as well as K 2P channel compositions may render mHb ChNs’ pace-making activity insensitive to histamine.…”

Section: Discussionmentioning

confidence: 99%

Chronic sleep fragmentation enhances habenula cholinergic neural activity

Guo

et al. 2019

Mol Psychiatry

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Sleep is essential to emotional health. Sleep disturbance, particularly REM sleep disturbance, profoundly impacts emotion regulation, but the underlying neural mechanisms remain elusive. Here we show that chronic REM sleep disturbance, achieved in mice by chronic sleep fragmentation (SF), enhanced neural activity in the medial habenula (mHb), a brain region increasingly implicated in negative affect. Specifically, after a 5-day SF procedure that selectively fragmented REM sleep, cholinergic output neurons (ChNs) in the mHb exhibited increased spontaneous firing rate and enhanced firing regularity in brain slices. The SF-induced firing changes remained intact upon inhibition of glutamate, GABA, acetylcholine, and histamine receptors, suggesting cell-autonomous mechanisms independent of synaptic transmissions. Moreover, the SF-induced hyperactivity was not because of enhanced intrinsic membrane excitability, but was accompanied by depolarized resting membrane potential in mHb ChNs. Furthermore, inhibition of TASK-3 (KCNK9) channels, a subtype of two-pore domain K+ channels, mimicked the SF effects by increasing the firing rate and regularity, as well as depolarizing the resting membrane potential in mHb ChNs in control-sleep mice. These effects of TASK-3 inhibition were absent in SF mice, suggesting reduced TASK-3 activity following SF. By contrast, inhibition of small-conductance Ca2+-activated K+ (SK) channels did not produce similar effects. Thus, SF compromised TASK-3 function in mHb ChNs, which likely led to depolarized resting membrane potential and increased spontaneous firing. These results not only demonstrate that selective REM sleep disturbance leads to hyperactivity of mHb ChNs, but also identify a key molecular substrate through which REM sleep disturbance may alter affect regulation.

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Section: Discussionmentioning

confidence: 99%

Chronic sleep fragmentation enhances habenula cholinergic neural activity

Guo

et al. 2019

Mol Psychiatry

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“…Deficiency of TWIK-1 induced with specific short hairpin RNA (shRNA) results in increased RMP, which increases the excitability of hippocampal dentate gyrus (DG) granule neurons [7,8]. Additionally, TWIK-1 is a key component of astrocytic passive conductance, which is important for potassium buffering [9][10][11][12]. Therefore, these previous studies strongly suggest the important physiological roles of TWIK-1 channels in various tissues including the brain.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, TWIK-1 knockout mice show defects in phosphate transport in the proximal tubule and water transport in the medullary collecting duct of the kidney, as well as hyperpolarization in the resting membrane potential of pancreatic cells [5,6]. In addition, we recently reported that TWIK-1 contributes to maintaining proper neuronal excitability and astrocytic passive conductance in the mouse hippocampus [7][8][9][10][11]. Deficiency of TWIK-1 induced with specific short hairpin RNA (shRNA) results in increased RMP, which increases the excitability of hippocampal dentate gyrus (DG) granule neurons [7,8].…”

Section: Introductionmentioning

confidence: 99%

TWIK-1 BAC-GFP Transgenic Mice, an Animal Model for TWIK-1 Expression

Kwon

Yang

Kim

et al. 2021

Cells

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TWIK-1 is the first identified member of the two-pore domain potassium (K2P) channels that are involved in neuronal excitability and astrocytic passive conductance in the brain. Despite the physiological roles of TWIK-1, there is still a lack of information on the basic expression patterns of TWIK-1 proteins in the brain. Here, using a modified bacterial artificial chromosome (BAC), we generated a transgenic mouse (Tg mouse) line expressing green fluorescent protein (GFP) under the control of the TWIK-1 promoter (TWIK-1 BAC-GFP Tg mice). We confirmed that nearly all GFP-producing cells co-expressed endogenous TWIK-1 in the brain of TWIK-1 BAC-GFP Tg mice. GFP signals were highly expressed in various brain areas, including the dentate gyrus (DG), lateral entorhinal cortex (LEC), and cerebellum (Cb). In addition, we found that GFP signals were highly expressed in immature granule cells in the DG. Finally, our TWIK-1 BAC-GFP Tg mice mimic the upregulation of TWIK-1 mRNA expression in the hippocampus following the injection of kainic acid (KA). Our data clearly showed that TWIK-1 BAC-GFP Tg mice are a useful animal model for studying the mechanisms regulating TWIK-1 gene expression and the physiological roles of TWIK-1 channels in the brain.

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“…PD-1 is expressed on activated CD4 + and CD8 + T-cells and interaction of PD-1 with its ligands results in the suppression of T-cell sensitivity to antigenic stimulation 23 , 24 . Tim-3 is mainly present on Th1 (helper T-cell 1) and Tc1 (cytotoxic T-cell 1) subsets, but it is also expressed on innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and monocytes 25 .…”

Section: Introductionmentioning

confidence: 99%

“…In chronic HIV, HBV, and HCV infection, elevated PD-1 and/or Tim-3 expression characterize subpopulations of both total and virus-specific exhausted T-cells 9 , 17 , 28 , 29 . Functional exhaustion can be reversed by blocking of interactions of iRs with their ligands 23 , 27 , 30 – 32 , but exclusive blockade of the PD-1 pathway with specific monoclonal antibodies does not fully restore cell functionality. McMahan et al 17 showed that blocking of either the PD-1 or Tim-3 pathway enhances proliferation of HCV-specific CD8 + T-cells in vitro, whereas cytotoxicity against a hepatocyte cell line expressing cognate HCV epitopes was increased exclusively by Tim-3 blocking.…”

Section: Introductionmentioning

confidence: 99%

Decrease of T-cells exhaustion markers programmed cell death-1 and T-cell immunoglobulin and mucin domain-containing protein 3 and plasma IL-10 levels after successful treatment of chronic hepatitis C

Osuch

Laskus

Berak³

et al. 2020

Sci Rep

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During chronic hepatitis C virus (HCV) infection, both CD4+ and CD8+ T-cells become functionally exhausted, which is reflected by increased expression of programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and elevated anti-inflammatory interleukin 10 (IL-10) plasma levels. We studied 76 DAA-treated HCV-positive patients and 18 non-infected controls. Flow cytometry measured pretreatment frequencies of CD4+PD-1+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cells and IL-10 levels measured by ELISA were significantly higher and CD4+PD-1−Tim-3− and CD8+PD-1−Tim-3− T-cells were significantly lower in patients than in controls. Treatment resulted in significant decrease of CD4+Tim-3+, CD8+Tim-3+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cell frequencies as well as IL-10 levels and increase in CD4+PD-1−Tim-3− and CD8+PD-1−Tim-3− T-cells. There were no significant changes in the frequencies of CD4+PD-1+ T-cells, while CD8+PD-1+ T-cells increased. Patients with advanced liver fibrosis had higher PD-1 and lower Tim-3 expression on CD4+T-cells and treatment had little or no effect on the exhaustion markers. HCV-specific CD8+T-cells frequency has declined significantly after treatment, but their PD-1 and Tim-3 expression did not change. Successful treatment of chronic hepatitis C with DAA is associated with reversal of immune exhaustion phenotype, but this effect is absent in patients with advanced liver fibrosis.

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Emerging Roles of TWIK-1 Heterodimerization in the Brain

Cited by 9 publications

References 50 publications

Chronic sleep fragmentation enhances habenula cholinergic neural activity

Chronic sleep fragmentation enhances habenula cholinergic neural activity

TWIK-1 BAC-GFP Transgenic Mice, an Animal Model for TWIK-1 Expression

Decrease of T-cells exhaustion markers programmed cell death-1 and T-cell immunoglobulin and mucin domain-containing protein 3 and plasma IL-10 levels after successful treatment of chronic hepatitis C

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