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The CaMKII/MLC1 Axis Confers Ca(2+)-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes

Astrocytes, the main glial cells of the central nervous system, play a key role in brain volume control due to their intimate contacts with cerebral blood vessels and the expression of a distinctive equipment of proteins involved in solute/water transport. Among these is MLC1, a protein highly expre...

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Autores principales: Brignone, Maria Stefania, Lanciotti, Angela, Michelucci, Antonio, Mallozzi, Cinzia, Camerini, Serena, Catacuzzeno, Luigi, Sforna, Luigi, Caramia, Martino, D’Adamo, Maria Cristina, Ceccarini, Marina, Molinari, Paola, Macioce, Pompeo, Macchia, Gianfranco, Petrucci, Tamara Corinna, Pessia, Mauro, Visentin, Sergio, Ambrosini, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454758/
https://www.ncbi.nlm.nih.gov/pubmed/36078064
http://dx.doi.org/10.3390/cells11172656
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author Brignone, Maria Stefania
Lanciotti, Angela
Michelucci, Antonio
Mallozzi, Cinzia
Camerini, Serena
Catacuzzeno, Luigi
Sforna, Luigi
Caramia, Martino
D’Adamo, Maria Cristina
Ceccarini, Marina
Molinari, Paola
Macioce, Pompeo
Macchia, Gianfranco
Petrucci, Tamara Corinna
Pessia, Mauro
Visentin, Sergio
Ambrosini, Elena
author_facet Brignone, Maria Stefania
Lanciotti, Angela
Michelucci, Antonio
Mallozzi, Cinzia
Camerini, Serena
Catacuzzeno, Luigi
Sforna, Luigi
Caramia, Martino
D’Adamo, Maria Cristina
Ceccarini, Marina
Molinari, Paola
Macioce, Pompeo
Macchia, Gianfranco
Petrucci, Tamara Corinna
Pessia, Mauro
Visentin, Sergio
Ambrosini, Elena
author_sort Brignone, Maria Stefania
collection PubMed
description Astrocytes, the main glial cells of the central nervous system, play a key role in brain volume control due to their intimate contacts with cerebral blood vessels and the expression of a distinctive equipment of proteins involved in solute/water transport. Among these is MLC1, a protein highly expressed in perivascular astrocytes and whose mutations cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), an incurable leukodystrophy characterized by macrocephaly, chronic brain edema, cysts, myelin vacuolation, and astrocyte swelling. Although, in astrocytes, MLC1 mutations are known to affect the swelling-activated chloride currents (ICl,(swell)) mediated by the volume-regulated anion channel (VRAC), and the regulatory volume decrease, MLC1′s proper function is still unknown. By combining molecular, biochemical, proteomic, electrophysiological, and imaging techniques, we here show that MLC1 is a Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) target protein, whose phosphorylation, occurring in response to intracellular Ca(2+) release, potentiates VRAC-mediated ICl,(swell). Overall, these findings reveal that MLC1 is a Ca(2+)-regulated protein, linking volume regulation to Ca(2+) signaling in astrocytes. This knowledge provides new insight into the MLC1 protein function and into the mechanisms controlling ion/water exchanges in the brain, which may help identify possible molecular targets for the treatment of MLC and other pathological conditions caused by astrocyte swelling and brain edema.
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spelling pubmed-94547582022-09-09 The CaMKII/MLC1 Axis Confers Ca(2+)-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes Brignone, Maria Stefania Lanciotti, Angela Michelucci, Antonio Mallozzi, Cinzia Camerini, Serena Catacuzzeno, Luigi Sforna, Luigi Caramia, Martino D’Adamo, Maria Cristina Ceccarini, Marina Molinari, Paola Macioce, Pompeo Macchia, Gianfranco Petrucci, Tamara Corinna Pessia, Mauro Visentin, Sergio Ambrosini, Elena Cells Article Astrocytes, the main glial cells of the central nervous system, play a key role in brain volume control due to their intimate contacts with cerebral blood vessels and the expression of a distinctive equipment of proteins involved in solute/water transport. Among these is MLC1, a protein highly expressed in perivascular astrocytes and whose mutations cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), an incurable leukodystrophy characterized by macrocephaly, chronic brain edema, cysts, myelin vacuolation, and astrocyte swelling. Although, in astrocytes, MLC1 mutations are known to affect the swelling-activated chloride currents (ICl,(swell)) mediated by the volume-regulated anion channel (VRAC), and the regulatory volume decrease, MLC1′s proper function is still unknown. By combining molecular, biochemical, proteomic, electrophysiological, and imaging techniques, we here show that MLC1 is a Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) target protein, whose phosphorylation, occurring in response to intracellular Ca(2+) release, potentiates VRAC-mediated ICl,(swell). Overall, these findings reveal that MLC1 is a Ca(2+)-regulated protein, linking volume regulation to Ca(2+) signaling in astrocytes. This knowledge provides new insight into the MLC1 protein function and into the mechanisms controlling ion/water exchanges in the brain, which may help identify possible molecular targets for the treatment of MLC and other pathological conditions caused by astrocyte swelling and brain edema. MDPI 2022-08-26 /pmc/articles/PMC9454758/ /pubmed/36078064 http://dx.doi.org/10.3390/cells11172656 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Brignone, Maria Stefania
Lanciotti, Angela
Michelucci, Antonio
Mallozzi, Cinzia
Camerini, Serena
Catacuzzeno, Luigi
Sforna, Luigi
Caramia, Martino
D’Adamo, Maria Cristina
Ceccarini, Marina
Molinari, Paola
Macioce, Pompeo
Macchia, Gianfranco
Petrucci, Tamara Corinna
Pessia, Mauro
Visentin, Sergio
Ambrosini, Elena
The CaMKII/MLC1 Axis Confers Ca(2+)-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes
title The CaMKII/MLC1 Axis Confers Ca(2+)-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes
title_full The CaMKII/MLC1 Axis Confers Ca(2+)-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes
title_fullStr The CaMKII/MLC1 Axis Confers Ca(2+)-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes
title_full_unstemmed The CaMKII/MLC1 Axis Confers Ca(2+)-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes
title_short The CaMKII/MLC1 Axis Confers Ca(2+)-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes
title_sort camkii/mlc1 axis confers ca(2+)-dependence to volume-regulated anion channels (vrac) in astrocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454758/
https://www.ncbi.nlm.nih.gov/pubmed/36078064
http://dx.doi.org/10.3390/cells11172656
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