A growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology

Wie, Jinhong; Liu, Zhenjiang; Song, Haikun; Tropea, Thomas F.; Lü, Yang; Wang, Huanhuan; Liang, Yuling; Cang, Chunlei; Aranda, Kimberly; Lohmann, Joey; Yang, Jing; Lu, Boxun; Chen‐Plotkin, Alice S.; Luk, Kelvin C.; Ren, Dejian

doi:10.1038/s41586-021-03185-z

Cited by 82 publications

(114 citation statements)

References 86 publications

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Section: Resultsmentioning

confidence: 99%

“…It has recently been described that PKB directly binds to TMEM175, the channel is opened by the conformational changes of PKB, and the regulation does not require the enzymatic activity of the kinase [ 14 ]. The PKB activator SC79, and allosteric PKB inhibitor MK2206 were reported to change TMEM175 current via the interaction with PKB associated to the channel [ 14 ]. SC79 binds to the pleckstrin homology (PH) domain of PKB, stabilizes the active ‘open’ conformation of the kinase, and causes channel opening via the conformational coupling between the two proteins (for schematic illustration, Figure 8 A) [ 14 ].…”

Section: Resultsmentioning

confidence: 99%

“…The PKB activator SC79, and allosteric PKB inhibitor MK2206 were reported to change TMEM175 current via the interaction with PKB associated to the channel [ 14 ]. SC79 binds to the pleckstrin homology (PH) domain of PKB, stabilizes the active ‘open’ conformation of the kinase, and causes channel opening via the conformational coupling between the two proteins (for schematic illustration, Figure 8 A) [ 14 ]. PKB was also reported to enhance the plasma membrane insertion of different ion channel types, including potassium channels [ 36 , 37 , 38 ].…”

Section: Resultsmentioning

confidence: 99%

“…MK2206 (20 μM, 20 h) allosteric PKB inhibitor caused about 80% inhibition of TMEM175 current induced by dyngo-4a ( Figure 8 B,C, fourth vs. fifth columns , p < 0.05). Based on the reported model [ 14 ], MK2206 inhibits TMEM175, since it simultaneously binds to the PH and near the catalytic domain of PKB and stabilizes the inactive ‘closed’ conformation of the kinase and (consequently) the channel ( Figure 8 A). The substantial inhibition of TMEM175 current by MK2206 in the presence of dyngo-4a may be caused by the inhibition of the active TMEM175-PKB complex by MK2206 in the plasma membrane, or by the interference of MK2206 with the effect of dyngo-4a.…”

Section: Resultsmentioning

confidence: 99%

“…TMEM175 has recently been identified as the ubiquitous K + channel of endosomal and lysosomal membranes [ 10 ]. Despite its importance, only a few studies have been reported about the electrophysiological properties of TMEM175 [ 10 , 11 , 12 , 13 , 14 ], in part because of the problematic accessibility of the native channel in the intracellular organelles. TMEM175 has an unusual ion selectivity profile, as determined in patch clamp measurements of endosomes enlarged by Rab5-Q79L transfection.…”

Section: Introductionmentioning

confidence: 99%

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Translocation of TMEM175 Lysosomal Potassium Channel to the Plasma Membrane by Dynasore Compounds

Pergel

Veres

Csigi

et al. 2021

IJMS

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TMEM175 (transmembrane protein 175) coding sequence variants are associated with increased risk of Parkinson’s disease. TMEM175 is the ubiquitous lysosomal K+ channel regulated by growth factor receptor signaling and direct interaction with protein kinase B (PKB/Akt). In the present study, we show that the expression of mouse TMEM175 results in very small K+ currents through the plasma membrane in Xenopus laevis oocytes, in good accordance with the previously reported intracellular localization of the channel. However, the application of the dynamin inhibitor compounds, dynasore or dyngo-4a, substantially increased TMEM175 currents measured by the two-electrode voltage clamp method. TMEM175 was more permeable to cesium than potassium ions, voltage-dependently blocked by 4-aminopyridine (4-AP), and slightly inhibited by extracellular acidification. Immunocytochemistry experiments indicated that dyngo-4a increased the amount of epitope-tagged TMEM175 channel on the cell surface. The coexpression of dominant-negative dynamin, and the inhibition of clathrin- or caveolin-dependent endocytosis increased TMEM175 current much less than dynasore. Therefore, dynamin-independent pharmacological effects of dynasore may also contribute to the action on the channel. TMEM175 current rapidly decays after the withdrawal of dynasore, raising the possibility that an efficient internalization mechanism removes the channel from the plasma membrane. Dyngo-4a induced about 20-fold larger TMEM175 currents than the PKB activator SC79, or the coexpression of a constitutively active mutant PKB with the channel. In contrast, the allosteric PKB inhibitor MK2206 diminished the TMEM175 current in the presence of dyngo-4a. These data suggest that, in addition to the lysosomes, PKB-dependent regulation also influences TMEM175 current in the plasma membrane.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Translocation of TMEM175 Lysosomal Potassium Channel to the Plasma Membrane by Dynasore Compounds

Pergel

Veres

Csigi

et al. 2021

IJMS

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Tubulin deacetylase NDST3 modulates lysosomal acidification: Implications in neurological diseases

Tang

Wang

2022

BioEssays

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Neurological diseases (NDs), featured by progressive dysfunctions of the nervous system, have become a growing burden for the aging populations. N‐Deacetylase and N‐sulfotransferase 3 (NDST3) is known to catalyze deacetylation and N‐sulfation on disaccharide substrates. Recently, NDST3 is identified as a novel deacetylase for tubulin, and its newly recognized role in modulating microtubule acetylation and lysosomal acidification provides fresh insights into ND therapeutic approaches using NDST3 as a target. Microtubule acetylation and lysosomal acidification have been reported to be critical for activities in neurons, implying that the regulators of these two biological processes, such as the previously known microtubule deacetylases, histone deacetylase 6 (HDAC6) and sirtuin 2 (SIRT2), could play important roles in various NDs. Aberrant NDST3 expression or tubulin acetylation has been observed in an increasing number of NDs, including amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), schizophrenia and bipolar disorder, Alzheimer's disease (AD), and Parkinson's disease (PD), suggesting that NDST3 is a key player in the pathogenesis of NDs and may serve as a target for development of new treatment of NDs.

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TMEM175 downregulation participates in impairment of the autophagy related lysosomal dynamics following neonatal hypoxic‐ischemic brain injury

Zhang,

Tian,

et al. 2023

Journal Cellular Physiology

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The mechanism underlying long‐term cognitive impairment caused by neonatal hypoxic‐ischemic brain injury (HIBI) remains unclear. Autophagy is a closely related mechanism and may play a role in this process. We aimed to investigate the role of lysosomal transmembrane protein 175 (TMEM175) in the autophagy‐lysosome pathway in neonatal rats with HIBI. A neonatal rat model of HIBI was established, hypoxia was induced, followed by left common carotid artery ligation. Expression levels of TMEM175 and the corresponding proteins involved in autophagy flux and the endolysosomal system fusion process were measured. Rats were administered TMEM175 plasmid via intracerebroventricular injection to induce overexpression. Brain damage and cognitive function were then assessed. TMEM175 was downregulated in the hippocampal tissue, and the autophagy‐lysosome pathway was impaired following HIBI in neonatal rats. Overexpression of TMEM175 significantly mitigated neuronal injury and improved long‐term cognitive and memory function in neonatal rats with HIBI. We found that improvement in the autophagy‐lysosome pathway and endolysosomal system homeostasis, which are TMEM175 related, occurred via regulation of lysosomal membrane dynamic fusion. TMEM175 plays a critical role in maintaining the autophagy‐lysosome pathway and endolysosomal homeostasis, contributing to the amelioration of neuronal injury and impaired long‐term cognitive function following neonatal HIBI.

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A growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology

Cited by 82 publications

References 86 publications

Translocation of TMEM175 Lysosomal Potassium Channel to the Plasma Membrane by Dynasore Compounds

Translocation of TMEM175 Lysosomal Potassium Channel to the Plasma Membrane by Dynasore Compounds

Tubulin deacetylase NDST3 modulates lysosomal acidification: Implications in neurological diseases

TMEM175 downregulation participates in impairment of the autophagy related lysosomal dynamics following neonatal hypoxic‐ischemic brain injury

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