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Characterization of two pathological gating-charge substitutions in Cav1.4 L-type calcium channels.
Heigl, Thomas; Netzer, Michael A; Zanetti, Lucia; Ganglberger, Matthias; Fernández-Quintero, Monica L; Koschak, Alexandra.
Afiliação
  • Heigl T; University of Innsbruck, Institute of Pharmacy, Pharmacology and Toxicology, Innsbruck, Austria.
  • Netzer MA; University of Innsbruck, Institute of Pharmacy, Pharmacology and Toxicology, Innsbruck, Austria.
  • Zanetti L; University of Innsbruck, Institute of Pharmacy, Pharmacology and Toxicology, Innsbruck, Austria.
  • Ganglberger M; University of Innsbruck, Institute of Pharmacy, Pharmacology and Toxicology, Innsbruck, Austria.
  • Fernández-Quintero ML; Institute of General, Inorganic and Theoretical Chemistry, Center for Chemistry and Biomedicine, University of Innsbruck, Innsbruck, Austria.
  • Koschak A; Division of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria.
Channels (Austin) ; 17(1): 2192360, 2023 12.
Article em En | MEDLINE | ID: mdl-36943941
ABSTRACT
Cav1.4 L-type calcium channels are predominantly expressed at the photoreceptor terminals and in bipolar cells, mediating neurotransmitter release. Mutations in its gene, CACNA1F, can cause congenital stationary night-blindness type 2 (CSNB2). Due to phenotypic variability in CSNB2, characterization of pathological variants is necessary to better determine pathological mechanism at the site of action. A set of known mutations affects conserved gating charges in the S4 voltage sensor, two of which have been found in male CSNB2 patients. Here, we describe two disease-causing Cav1.4 mutations with gating charge neutralization, exchanging an arginine 964 with glycine (RG) or arginine 1288 with leucine (RL). In both, charge neutralization was associated with a reduction channel expression also reflected in smaller ON gating currents. In RL channels, the strong decrease in whole-cell current densities might additionally be explained by a reduction of single-channel currents. We further identified alterations in their biophysical properties, such as a hyperpolarizing shift of the activation threshold and an increase in slope factor of activation and inactivation. Molecular dynamic simulations in RL substituted channels indicated water wires in both, resting and active, channel states, suggesting the development of omega (ω)currents as a new pathological mechanism in CSNB2. This sum of the respective channel property alterations might add to the differential symptoms in patients beside other factors, such as genomic and environmental deviations.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oftalmopatias Hereditárias / Cegueira Noturna / Miopia Tipo de estudo: Prognostic_studies Limite: Humans / Male Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oftalmopatias Hereditárias / Cegueira Noturna / Miopia Tipo de estudo: Prognostic_studies Limite: Humans / Male Idioma: En Ano de publicação: 2023 Tipo de documento: Article