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Membranes (Basel) 2023 Jan 11;131:. doi: 10.3390/membranes13010096.
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Functional Characterization of Four Known Cav2.1 Variants Associated with Neurodevelopmental Disorders.

Folacci M , Estaran S , Ménard C , Bertaud A , Rousset M , Roussel J , Thibaud JB , Vignes M , Chavanieu A , Charnet P , Cens T .

Cav2.1 channels are expressed throughout the brain and are the predominant Ca2+ 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.

PubMed ID: 36676903
PMC ID: PMC9864995
Article link: Membranes (Basel)

Species referenced: Xenopus laevis
Genes referenced: cav2
GO keywords: calcium channel activity [+]

Article Images: [+] show captions
References [+] :
Adams, Ca(V)2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies. 2009, Pubmed