Full text

Turn on search term navigation

© 2022 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 (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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 Ca2+/Calmodulin-dependent protein kinase II (CaMKII) target protein, whose phosphorylation, occurring in response to intracellular Ca2+ release, potentiates VRAC-mediated ICl,swell. Overall, these findings reveal that MLC1 is a Ca2+-regulated protein, linking volume regulation to Ca2+ 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.

Details

Title
The CaMKII/MLC1 Axis Confers Ca2+-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes
Author
Brignone, Maria Stefania 1 ; Lanciotti, Angela 1   VIAFID ORCID Logo  ; Michelucci, Antonio 2 ; Mallozzi, Cinzia 1   VIAFID ORCID Logo  ; Camerini, Serena 3 ; Catacuzzeno, Luigi 2 ; Sforna, Luigi 2   VIAFID ORCID Logo  ; Caramia, Martino 2 ; Maria Cristina D’Adamo 4   VIAFID ORCID Logo  ; Ceccarini, Marina 5 ; Molinari, Paola 6 ; Macioce, Pompeo 1   VIAFID ORCID Logo  ; Macchia, Gianfranco 3   VIAFID ORCID Logo  ; Petrucci, Tamara Corinna 1 ; Pessia, Mauro 7   VIAFID ORCID Logo  ; Visentin, Sergio 6 ; Ambrosini, Elena 1   VIAFID ORCID Logo 

 Department of Neuroscience, Istituto Superiore di Sanità, 00169 Rome, Italy 
 Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy 
 Core Facilities (FAST), Istituto Superiore di Sanità, 00169 Rome, Italy 
 Department of Medicine and Surgery, LUM Giuseppe Degennaro University, 70010 Bari, Italy 
 National Centre for Rare Diseases, Istituto Superiore di Sanità, 00169 Rome, Italy 
 National Centre for Drug Research and Evaluation (FARVA), Istituto Superiore di Sanità, 00169 Rome, Italy 
 Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, MSD2080 Msida, Malta; Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates 
First page
2656
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
20734409
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2711283620
Copyright
© 2022 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 (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.