dc.contributor.author |
Bahamonde, María Isabel |
dc.contributor.author |
Serra, Selma Angèlica |
dc.contributor.author |
Drechsel, Oliver |
dc.contributor.author |
Rahman, Rubayte |
dc.contributor.author |
Marcé-Grau, Anna |
dc.contributor.author |
Prieto, Marta |
dc.contributor.author |
Ossowski, Stephan |
dc.contributor.author |
Macaya Ruiz, Alfons |
dc.contributor.author |
Fernández-Fernández, José M. |
dc.contributor.author |
Universitat Autònoma de Barcelona |
dc.date |
2015 |
dc.identifier |
https://ddd.uab.cat/record/254509 |
dc.identifier |
urn:10.1371/journal.pone.0146035 |
dc.identifier |
urn:oai:ddd.uab.cat:254509 |
dc.identifier |
urn:pmcid:PMC4696675 |
dc.identifier |
urn:pmc-uid:4696675 |
dc.identifier |
urn:pmid:26716990 |
dc.identifier |
urn:oai:pubmedcentral.nih.gov:4696675 |
dc.identifier |
urn:oai:egreta.uab.cat:publications/7f2b15d4-930f-469e-98ed-a282bb9196e4 |
dc.identifier |
urn:scopus_id:84957600854 |
dc.format |
application/pdf |
dc.language |
eng |
dc.publisher |
|
dc.relation |
Ministerio de Economía y Competitividad SAF2012-31089 |
dc.relation |
Ministerio de Economía y Competitividad SEV-2012-0208 |
dc.relation |
Instituto de Salud Carlos III RD12/0042/0014 |
dc.relation |
Instituto de Salud Carlos III PI12/1005 |
dc.relation |
PloS one ; Vol. 10 (december 2015) |
dc.rights |
open access |
dc.rights |
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. |
dc.rights |
https://creativecommons.org/licenses/by/4.0/ |
dc.title |
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 |
dc.type |
Article |
dc.description.abstract |
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 |