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Functional Characterization of Four Known Cav2.1 Variants Associated with Neurodevelopmental Disorders

Cav2.1 channels are expressed throughout the brain and are the predominant Ca(2+) channels in the Purkinje cells. These cerebellar neurons fire spontaneously, and Cav2.1 channels are involved in the regular pacemaking activity. The loss of precision of the firing pattern of Purkinje cells leads to a...

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Autores principales: Folacci, Mathilde, Estaran, Sébastien, Ménard, Claudine, Bertaud, Anaïs, Rousset, Matthieu, Roussel, Julien, Thibaud, Jean-Baptiste, Vignes, Michel, Chavanieu, Alain, Charnet, Pierre, Cens, Thierry
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864995/
https://www.ncbi.nlm.nih.gov/pubmed/36676903
http://dx.doi.org/10.3390/membranes13010096
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author Folacci, Mathilde
Estaran, Sébastien
Ménard, Claudine
Bertaud, Anaïs
Rousset, Matthieu
Roussel, Julien
Thibaud, Jean-Baptiste
Vignes, Michel
Chavanieu, Alain
Charnet, Pierre
Cens, Thierry
author_facet Folacci, Mathilde
Estaran, Sébastien
Ménard, Claudine
Bertaud, Anaïs
Rousset, Matthieu
Roussel, Julien
Thibaud, Jean-Baptiste
Vignes, Michel
Chavanieu, Alain
Charnet, Pierre
Cens, Thierry
author_sort Folacci, Mathilde
collection PubMed
description Cav2.1 channels are expressed throughout the brain and are the predominant Ca(2+) channels in the Purkinje cells. These cerebellar neurons fire spontaneously, and Cav2.1 channels are involved in the regular pacemaking activity. The loss of precision of the firing pattern of Purkinje cells leads to ataxia, a disorder characterized by poor balance and difficulties in performing coordinated movements. In this study, we aimed at characterizing functional and structural consequences of four variations (p.A405T in I-II loop and p.R1359W, p.R1667W and p.S1799L in IIIS4, IVS4, and IVS6 helices, respectively) identified in patients exhibiting a wide spectrum of disorders including ataxia symptoms. Functional analysis using two major Cav2.1 splice variants (Cav2.1+e47 and Cav2.1−e47) in Xenopus laevis oocytes, revealed a lack of effect upon A405T substitution and a significant loss-of-function caused by R1359W, whereas R1667W and S1799L caused both channel gain-of-function and loss-of-function, in a splice variant-dependent manner. Structural analysis revealed the loss of interactions with S1, S2, and S3 helices upon R1359W and R1667W substitutions, but a lack of obvious structural changes with S1799L. Computational modeling suggests that biophysical changes induced by Cav2.1 pathogenic mutations might affect action potential frequency in Purkinje cells.
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spelling pubmed-98649952023-01-22 Functional Characterization of Four Known Cav2.1 Variants Associated with Neurodevelopmental Disorders Folacci, Mathilde Estaran, Sébastien Ménard, Claudine Bertaud, Anaïs Rousset, Matthieu Roussel, Julien Thibaud, Jean-Baptiste Vignes, Michel Chavanieu, Alain Charnet, Pierre Cens, Thierry Membranes (Basel) Article Cav2.1 channels are expressed throughout the brain and are the predominant Ca(2+) channels in the Purkinje cells. These cerebellar neurons fire spontaneously, and Cav2.1 channels are involved in the regular pacemaking activity. The loss of precision of the firing pattern of Purkinje cells leads to ataxia, a disorder characterized by poor balance and difficulties in performing coordinated movements. In this study, we aimed at characterizing functional and structural consequences of four variations (p.A405T in I-II loop and p.R1359W, p.R1667W and p.S1799L in IIIS4, IVS4, and IVS6 helices, respectively) identified in patients exhibiting a wide spectrum of disorders including ataxia symptoms. Functional analysis using two major Cav2.1 splice variants (Cav2.1+e47 and Cav2.1−e47) in Xenopus laevis oocytes, revealed a lack of effect upon A405T substitution and a significant loss-of-function caused by R1359W, whereas R1667W and S1799L caused both channel gain-of-function and loss-of-function, in a splice variant-dependent manner. Structural analysis revealed the loss of interactions with S1, S2, and S3 helices upon R1359W and R1667W substitutions, but a lack of obvious structural changes with S1799L. Computational modeling suggests that biophysical changes induced by Cav2.1 pathogenic mutations might affect action potential frequency in Purkinje cells. MDPI 2023-01-11 /pmc/articles/PMC9864995/ /pubmed/36676903 http://dx.doi.org/10.3390/membranes13010096 Text en © 2023 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
Folacci, Mathilde
Estaran, Sébastien
Ménard, Claudine
Bertaud, Anaïs
Rousset, Matthieu
Roussel, Julien
Thibaud, Jean-Baptiste
Vignes, Michel
Chavanieu, Alain
Charnet, Pierre
Cens, Thierry
Functional Characterization of Four Known Cav2.1 Variants Associated with Neurodevelopmental Disorders
title Functional Characterization of Four Known Cav2.1 Variants Associated with Neurodevelopmental Disorders
title_full Functional Characterization of Four Known Cav2.1 Variants Associated with Neurodevelopmental Disorders
title_fullStr Functional Characterization of Four Known Cav2.1 Variants Associated with Neurodevelopmental Disorders
title_full_unstemmed Functional Characterization of Four Known Cav2.1 Variants Associated with Neurodevelopmental Disorders
title_short Functional Characterization of Four Known Cav2.1 Variants Associated with Neurodevelopmental Disorders
title_sort functional characterization of four known cav2.1 variants associated with neurodevelopmental disorders
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864995/
https://www.ncbi.nlm.nih.gov/pubmed/36676903
http://dx.doi.org/10.3390/membranes13010096
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