{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T07:11:43Z","timestamp":1772694703566,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Secretar\u00eda de Educaci\u00f3n, Ciencia, Tecnolog\u00eda e Innovaci\u00f3n de la Ciudad de M\u00e9xico","award":["SECTEI\/146\/2024"],"award-info":[{"award-number":["SECTEI\/146\/2024"]}]},{"name":"Secretar\u00eda de Educaci\u00f3n, Ciencia, Tecnolog\u00eda e Innovaci\u00f3n de la Ciudad de M\u00e9xico","award":["IN211524"],"award-info":[{"award-number":["IN211524"]}]},{"name":"Programa de Apoyo a Proyectos de Investigaci\u00f3n e Innovaci\u00f3n Tecnol\u00f3gica (PAPIIT) at the National Autonomous University of Mexico (UNAM)","award":["SECTEI\/146\/2024"],"award-info":[{"award-number":["SECTEI\/146\/2024"]}]},{"name":"Programa de Apoyo a Proyectos de Investigaci\u00f3n e Innovaci\u00f3n Tecnol\u00f3gica (PAPIIT) at the National Autonomous University of Mexico (UNAM)","award":["IN211524"],"award-info":[{"award-number":["IN211524"]}]},{"name":"Direcci\u00f3n General de Asuntos del Personal Acad\u00e9mico (DGAPA-UNAM)","award":["SECTEI\/146\/2024"],"award-info":[{"award-number":["SECTEI\/146\/2024"]}]},{"name":"Direcci\u00f3n General de Asuntos del Personal Acad\u00e9mico (DGAPA-UNAM)","award":["IN211524"],"award-info":[{"award-number":["IN211524"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Voltage-gated Ca2+ (CaV) channels are transmembrane proteins comprising the pore-forming subunit CaV\u03b11 and the ancillary proteins CaV\u03b12\u03b4 and CaV\u03b2. They are expressed in various tissues, including the nervous system, where they regulate Ca2+ entry in response to membrane potential changes. The increase in intracellular Ca2+ allows for regulating cell excitability and releasing neurotransmitters, among other cellular events. Leucine-rich repeat kinase 2 (LRRK2) is a serine\u2013threonine kinase involved in vesicular mobilization. Previously, it has been shown that LRRK2 regulates neurotransmission by phosphorylating the CaV\u03b2 auxiliary subunit of the CaV2.1 (P\/Q-type) presynaptic channels. However, it is unknown whether the kinase can regulate the activity of other CaV channel subtypes, such as CaV1.3 (L-type), which play a significant role in the excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) and whose dysregulation contributes to neurodegeneration in Parkinson\u2019s disease (PD). Here, we found potential phosphorylation sites for LRRK2 in CaV\u03b23 and examined how these molecules interact. We used immunoprecipitation and electrophysiology in HEK-293 cells expressing recombinant CaV1.3 channels, both with and without wild-type LRRK2 or its LRRK2G2019S mutation, which plays a role in familial PD through a possible gain-of-toxic-function mechanism. Our results show that LRRK2G2019S significantly increases current density through CaV1.3 channels, and this effect depends on the presence of CaV\u03b23. Site-directed mutagenesis revealed that phosphorylation at S152 in the sequence of CaV\u03b23 is necessary and sufficient to explain the abnormal regulation of the channels mediated by LRRK2G2019S. These data provide new insights into the molecular regulation that mutant LRRK2 may exert on L-type CaV1.3 channels, which determine pacemaker activity in dopaminergic neurons of the SNc and may, therefore, play a relevant role in the molecular pathophysiology of PD.<\/jats:p>","DOI":"10.3390\/ijms26073229","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T03:25:02Z","timestamp":1743391502000},"page":"3229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Leucine-Rich Repeat Kinase 2 Variant LRRK2G2019S Up-Regulates L-Type (CaV1.3) Calcium Channel via the CaV\u03b23 Subunit: Possible Role in the Pathogenesis of Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Alejandro","family":"Sandoval","sequence":"first","affiliation":[{"name":"School of Medicine FES Iztacala, National Autonomous University of Mexico (UNAM), Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandra","family":"Corzo-L\u00f3pez","sequence":"additional","affiliation":[{"name":"School of Medicine FES Iztacala, National Autonomous University of Mexico (UNAM), Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8729-8636","authenticated-orcid":false,"given":"Paz","family":"Duran","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Tovar-Soto","sequence":"additional","affiliation":[{"name":"School of Medicine FES Iztacala, National Autonomous University of Mexico (UNAM), Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryan","family":"Vargas-Caballero","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Centre for Research and Advanced Studies (Cinvestav), Mexico City 077360, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Galicia-Salda\u00f1a","sequence":"additional","affiliation":[{"name":"School of Medicine FES Iztacala, National Autonomous University of Mexico (UNAM), Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1399-8036","authenticated-orcid":false,"given":"Ricardo","family":"Gonz\u00e1lez-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Histocaompatibility, \u201cDr. Manuel Gea Gonz\u00e1lez\u201d General Hospital, Mexico City 14080, Mexico"},{"name":"Center for Research on Aging, Cinvestav, Mexico City 14330, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5383-7176","authenticated-orcid":false,"given":"Ricardo","family":"Felix","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Centre for Research and Advanced Studies (Cinvestav), Mexico City 077360, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1146\/annurev.cellbio.16.1.521","article-title":"Structure and regulation of voltage-gated Ca2+ channels","volume":"16","author":"Catterall","year":"2000","journal-title":"Annu. 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