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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\u2032s 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.<\/jats:p>","DOI":"10.3390\/cells11172656","type":"journal-article","created":{"date-parts":[[2022,8,28]],"date-time":"2022-08-28T21:22:56Z","timestamp":1661721776000},"page":"2656","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The CaMKII\/MLC1 Axis Confers Ca2+-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes"],"prefix":"10.3390","volume":"11","author":[{"given":"Maria Stefania","family":"Brignone","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1615-1770","authenticated-orcid":false,"given":"Angela","family":"Lanciotti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Michelucci","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6126-9500","authenticated-orcid":false,"given":"Cinzia","family":"Mallozzi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Camerini","sequence":"additional","affiliation":[{"name":"Core Facilities (FAST), Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Catacuzzeno","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2145-3642","authenticated-orcid":false,"given":"Luigi","family":"Sforna","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martino","family":"Caramia","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6758-6064","authenticated-orcid":false,"given":"Maria Cristina","family":"D\u2019Adamo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, LUM Giuseppe Degennaro University, 70010 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Ceccarini","sequence":"additional","affiliation":[{"name":"National Centre for Rare Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Molinari","sequence":"additional","affiliation":[{"name":"National Centre for Drug Research and Evaluation (FARVA), Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1829-9448","authenticated-orcid":false,"given":"Pompeo","family":"Macioce","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6344-8724","authenticated-orcid":false,"given":"Gianfranco","family":"Macchia","sequence":"additional","affiliation":[{"name":"Core Facilities (FAST), Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara Corinna","family":"Petrucci","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2857-6795","authenticated-orcid":false,"given":"Mauro","family":"Pessia","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, MSD2080 Msida, Malta"},{"name":"Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. 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