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Ca(v)1.3 (CACNA1D) L‐type Ca(2+) channel dysfunction in CNS disorders

Ca(v)1.3 belongs to the family of voltage‐gated L‐type Ca(2+) channels and is encoded by the CACNA1D gene. Ca(v)1.3 channels are not only essential for cardiac pacemaking, hearing and hormone secretion but are also expressed postsynaptically in neurons, where they shape neuronal firing and plasticit...

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Autores principales: Pinggera, Alexandra, Striessnig, Jörg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823145/
https://www.ncbi.nlm.nih.gov/pubmed/26842699
http://dx.doi.org/10.1113/JP270672
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author Pinggera, Alexandra
Striessnig, Jörg
author_facet Pinggera, Alexandra
Striessnig, Jörg
author_sort Pinggera, Alexandra
collection PubMed
description Ca(v)1.3 belongs to the family of voltage‐gated L‐type Ca(2+) channels and is encoded by the CACNA1D gene. Ca(v)1.3 channels are not only essential for cardiac pacemaking, hearing and hormone secretion but are also expressed postsynaptically in neurons, where they shape neuronal firing and plasticity. Recent findings provide evidence that human mutations in the CACNA1D gene can confer risk for the development of neuropsychiatric disease and perhaps also epilepsy. Loss of Ca(v)1.3 function, as shown in knock‐out mouse models and by human mutations, does not result in neuropsychiatric or neurological disease symptoms, whereas their acute selective pharmacological activation results in a depressive‐like behaviour in mice. Therefore it is likely that CACNA1D mutations enhancing activity may be disease relevant also in humans. Indeed, whole exome sequencing studies, originally prompted to identify mutations in primary aldosteronism, revealed de novo CACNA1D missense mutations permitting enhanced Ca(2+) signalling through Ca(v)1.3. Remarkably, apart from primary aldosteronism, heterozygous carriers of these mutations also showed seizures and neurological abnormalities. Different missense mutations with very similar gain‐of‐function properties were recently reported in patients with autism spectrum disorders (ASD). These data strongly suggest that CACNA1D mutations enhancing Ca(v)1.3 activity confer a strong risk for – or even cause – CNS disorders, such as ASD. [Image: see text]
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spelling pubmed-48231452016-04-18 Ca(v)1.3 (CACNA1D) L‐type Ca(2+) channel dysfunction in CNS disorders Pinggera, Alexandra Striessnig, Jörg J Physiol Symposium section reviews: Voltage‐gated calcium channels ‐ from basic mechanisms to disease Ca(v)1.3 belongs to the family of voltage‐gated L‐type Ca(2+) channels and is encoded by the CACNA1D gene. Ca(v)1.3 channels are not only essential for cardiac pacemaking, hearing and hormone secretion but are also expressed postsynaptically in neurons, where they shape neuronal firing and plasticity. Recent findings provide evidence that human mutations in the CACNA1D gene can confer risk for the development of neuropsychiatric disease and perhaps also epilepsy. Loss of Ca(v)1.3 function, as shown in knock‐out mouse models and by human mutations, does not result in neuropsychiatric or neurological disease symptoms, whereas their acute selective pharmacological activation results in a depressive‐like behaviour in mice. Therefore it is likely that CACNA1D mutations enhancing activity may be disease relevant also in humans. Indeed, whole exome sequencing studies, originally prompted to identify mutations in primary aldosteronism, revealed de novo CACNA1D missense mutations permitting enhanced Ca(2+) signalling through Ca(v)1.3. Remarkably, apart from primary aldosteronism, heterozygous carriers of these mutations also showed seizures and neurological abnormalities. Different missense mutations with very similar gain‐of‐function properties were recently reported in patients with autism spectrum disorders (ASD). These data strongly suggest that CACNA1D mutations enhancing Ca(v)1.3 activity confer a strong risk for – or even cause – CNS disorders, such as ASD. [Image: see text] John Wiley and Sons Inc. 2016-02-29 2016-10-15 /pmc/articles/PMC4823145/ /pubmed/26842699 http://dx.doi.org/10.1113/JP270672 Text en © 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Symposium section reviews: Voltage‐gated calcium channels ‐ from basic mechanisms to disease
Pinggera, Alexandra
Striessnig, Jörg
Ca(v)1.3 (CACNA1D) L‐type Ca(2+) channel dysfunction in CNS disorders
title Ca(v)1.3 (CACNA1D) L‐type Ca(2+) channel dysfunction in CNS disorders
title_full Ca(v)1.3 (CACNA1D) L‐type Ca(2+) channel dysfunction in CNS disorders
title_fullStr Ca(v)1.3 (CACNA1D) L‐type Ca(2+) channel dysfunction in CNS disorders
title_full_unstemmed Ca(v)1.3 (CACNA1D) L‐type Ca(2+) channel dysfunction in CNS disorders
title_short Ca(v)1.3 (CACNA1D) L‐type Ca(2+) channel dysfunction in CNS disorders
title_sort ca(v)1.3 (cacna1d) l‐type ca(2+) channel dysfunction in cns disorders
topic Symposium section reviews: Voltage‐gated calcium channels ‐ from basic mechanisms to disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823145/
https://www.ncbi.nlm.nih.gov/pubmed/26842699
http://dx.doi.org/10.1113/JP270672
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