GlialCAM/MLC1 modulates LRRC8/VRAC currents in an indirect manner: Implications for megalencephalic leukoencephalopathy

Elorza‐Vidal, Xabier; Sirisi, Sònia; Gaitán‐Peñas, Héctor; Pérez-Rius, Carla; Alonso-Gardón, Marta; Armand‐Ugón, Mercedes; Lanciotti, Angela; Brignone, Maria Stefania; Prat, Esther; Nunes, Virginia; Ambrosini, Elena; Gasull, Xavier; Estévez, Raúl

doi:10.1016/j.nbd.2018.07.031

Cited by 35 publications

(42 citation statements)

References 59 publications

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“…Although Cx assembly and turnover are very complex processes involving many phosphorylation/dephosphorylation steps that are still incompletely known, several experimental evidences indicated that Cx43 phosphorylation by ERK1/2 and PKC on S262 and S279/282 amino acid residues induces channel closure and internalization, leading to a rapid shutdown of intercellular communication (see References [ 41 , 42 ] and the references therein). Considering the MLC1-mediated inhibition of ERK1/2 activation that we recently demonstrated in astrocytes [ 29 , 30 , 52 ], we thought possible that MLC1 hampered ERK1/2-induced phosphorylation of Cx43 and its consequent internalization in WT MLC1-expressing cells. To verify this possibility, we evaluated the effects of a specific pERK1/2 inhibitor (the PD98059) on Cx43 partitioning in Triton-insoluble compartments, finding out that pERK1/2 inhibition rescued Cx43 distribution in gap junctions in cells expressing the MLC1 mutants.…”

Section: Discussionmentioning

confidence: 97%

Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes

Lanciotti

Brignone

Belfiore

et al. 2020

Cells

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Astrocytes, the most numerous cells of the central nervous system, exert critical functions for brain homeostasis. To this purpose, astrocytes generate a highly interconnected intercellular network allowing rapid exchange of ions and metabolites through gap junctions, adjoined channels composed of hexamers of connexin (Cx) proteins, mainly Cx43. Functional alterations of Cxs and gap junctions have been observed in several neuroinflammatory/neurodegenerative diseases. In the rare leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC), astrocytes show defective control of ion/fluid exchanges causing brain edema, fluid cysts, and astrocyte/myelin vacuolation. MLC is caused by mutations in MLC1, an astrocyte-specific protein of elusive function, and in GlialCAM, a MLC1 chaperon. Both proteins are highly expressed at perivascular astrocyte end-feet and astrocyte-astrocyte contacts where they interact with zonula occludens-1 (ZO-1) and Cx43 junctional proteins. To investigate the possible role of Cx43 in MLC pathogenesis, we studied Cx43 properties in astrocytoma cells overexpressing wild type (WT) MLC1 or MLC1 carrying pathological mutations. Using biochemical and electrophysiological techniques, we found that WT, but not mutated, MLC1 expression favors intercellular communication by inhibiting extracellular-signal-regulated kinase 1/2 (ERK1/2)-mediated Cx43 phosphorylation and increasing Cx43 gap-junction stability. These data indicate MLC1 regulation of Cx43 in astrocytes and Cx43 involvement in MLC pathogenesis, suggesting potential target pathways for therapeutic interventions.

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Section: Discussionmentioning

confidence: 97%

Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes

Lanciotti

Brignone

Belfiore

et al. 2020

Cells

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“…It was recently shown that VRAC-forming LRRC8 plays a role in glucose sensing and the regulation of insulin secretion from beta cells [203]. Whether LRRC8 is regulated by GLP-1/cAMP is unknown but ERK1/2 appears to play a role in its phosphorylation [204] and ERK1/2 is activated by glucose and GLP-1 [205]. Thus, it is possible to speculate that LRRC8 might be regulated by interactions of glucose-and GLP-1 signaling to enhance excitability.…”

Section: B: Changes In Cell Excitabilitymentioning

confidence: 99%

New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

Tomás

Jones

Leech

2020

Journal of Molecular Biology

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Recent studies in cultured astrocytes have found that LRRC8 proteins are indispensable for the swelling-induced and ATP-induced release of neuroactive molecules like taurine, glutamate, aspartate, and myo-inositol, suggesting that different combinations of LRRC8 isoforms could form independent pathways for charged and uncharged molecules [104,105]. Furthermore, VRAC currents were also reduced after LRRC8A depletion [123,124]. Given that the molecular correlates of the VRAC have only recently been discovered, and given the poor pharmacological tools available alongside the absence of specific inhibitors of VRAC activity, the physiological and pathophysiological contribution of the astrocytic VRAC in the brain remains poorly understood.…”

Section: The Volume-regulated Anion-channel (Vrac)mentioning

confidence: 99%

“…As mentioned in the ClC-2 channel section, K + -siphoning requires associated Cl − fluxes to guarantee the electroneutrality of the process, and MLC1-GlialCAM-ClC-2 have been found to form a ternary complex that could be important for this purpose [53]. Interestingly, Mlc1 KO and knockdown astrocytes (and also GlialCAM knockdown) show reduced VRAC activity [124,127,128]. These studies suggested that the functional link between MLC1 and the VRAC could happen in an indirect manner involving signalling cascades.…”

Section: The Volume-regulated Anion-channel (Vrac)mentioning

confidence: 99%

Chloride Channels in Astrocytes: Structure, Roles in Brain Homeostasis and Implications in Disease

Elorza‐Vidal

Gaitán‐Peñas

Estévez

2019

IJMS

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Astrocytes are the most abundant cell type in the CNS (central nervous system). They exert multiple functions during development and in the adult CNS that are essential for brain homeostasis. Both cation and anion channel activities have been identified in astrocytes and it is believed that they play key roles in astrocyte function. Whereas the proteins and the physiological roles assigned to cation channels are becoming very clear, the study of astrocytic chloride channels is in its early stages. In recent years, we have moved from the identification of chloride channel activities present in astrocyte primary culture to the identification of the proteins involved in these activities, the determination of their 3D structure and attempts to gain insights about their physiological role. Here, we review the recent findings related to the main chloride channels identified in astrocytes: the voltage-dependent ClC-2, the calcium-activated bestrophin, the volume-activated VRAC (volume-regulated anion channel) and the stress-activated Maxi-Cl−. We discuss key aspects of channel biophysics and structure with a focus on their role in glial physiology and human disease.

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GlialCAM/MLC1 modulates LRRC8/VRAC currents in an indirect manner: Implications for megalencephalic leukoencephalopathy

Cited by 35 publications

References 59 publications

Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes

Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes

New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

Chloride Channels in Astrocytes: Structure, Roles in Brain Homeostasis and Implications in Disease

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