A Single Amino Acid Deletion (ΔF1502) in the S6 Segment of Ca2.1 Domain III Associated with Congenital Ataxia Increases Channel Activity and Promotes Ca 2+ Influx
Bahamonde, María Isabel (Universitat Pompeu Fabra)
Serra, Selma Angèlica (Universitat Pompeu Fabra)
Drechsel, Oliver (Universitat Pompeu Fabra)
Rahman, Rubayte (Universitat Pompeu Fabra)
Marcé-Grau, Anna (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Prieto, Marta (Universitat Pompeu Fabra)
Ossowski, Stephan (Universitat Pompeu Fabra)
Macaya Ruiz, Alfons (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Fernández-Fernández, José M. (Universitat Pompeu Fabra)
Universitat Autònoma de Barcelona

Fecha:	2015
Resumen:	Mutations in the CACNA1A gene, encoding the pore-forming Ca2. 1 (P/Q-type) channel α subunit, result in heterogeneous human neurological disorders, including familial and sporadic hemiplegic migraine along with episodic and progressive forms of ataxia. Hemiplegic Migraine (HM) mutations induce gain-of-channel function, mainly by shifting channel activation to lower voltages, whereas ataxia mutations mostly produce loss-of-channel function. However, some HM-linked gain-of-function mutations are also associated to congenital ataxia and/or cerebellar atrophy, including the deletion of a highly conserved phenylalanine located at the S6 pore region of α domain III (ΔF1502). Functional studies of ΔF1502 Ca2. 1 channels, expressed in Xenopus oocytes, using the non-physiological Ba 2+ as the charge carrier have only revealed discrete alterations in channel function of unclear pathophysiological relevance. Here, we report a second case of congenital ataxia linked to the ΔF1502 α mutation, detected by whole-exome sequencing, and analyze its functional consequences on Ca2. 1 human channels heterologously expressed in mammalian tsA-201 HEK cells, using the physiological permeant ion Ca 2+. ΔF1502 strongly decreases the voltage threshold for channel activation (by ~ 21 mV), allowing significantly higher Ca 2+ current densities in a range of depolarized voltages with physiological relevance in neurons, even though maximal Ca 2+ current density through ΔF1502 Ca2. 1 channels is 60% lower than through wild-type channels. ΔF1502 accelerates activation kinetics and slows deactivation kinetics of Ca2. 1 within a wide range of voltage depolarization. ΔF1502 also slowed Ca2. 1 inactivation kinetic and shifted the inactivation curve to hyperpolarized potentials (by ~ 28 mV). ΔF1502 effects on Ca2. 1 activation and deactivation properties seem to be of high physiological relevance. Thus, ΔF1502 strongly promotes Ca 2+ influx in response to either single or trains of action potential-like waveforms of different durations. Our observations support a causative role of gain-of-function Ca2. 1 mutations in congenital ataxia, a neurodevelopmental disorder at the severe-most end of CACNA1A -associated phenotypic spectrum.
Ayudas:	Ministerio de Economía y Competitividad SAF2012-31089 Ministerio de Economía y Competitividad SEV-2012-0208 Instituto de Salud Carlos III RD12/0042/0014 Instituto de Salud Carlos III PI12/1005
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	PloS one, Vol. 10 (december 2015) , ISSN 1932-6203

DOI: 10.1371/journal.pone.0146035
PMID: 26716990

28 p, 5.7 MB

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