Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis

Ginevra Zanni, Tito Calì, Vera M. Kalscheuer, Denis Ottolini, Sabina Barresi, Nicolas Lebrun, Luisa Montecchi-Palazzi, Hao Hu, Jamel Chelly, Enrico Bertini, Marisa Brini, Ernesto Carafoli

Research output: Contribution to journalArticle

Abstract

Ca2+ in neurons is vital to processes such as neurotransmission, neurotoxicity, synaptic development, and gene expression. Disruption of Ca 2+ homeostasis occurs in brain aging and in neurodegenerative disorders. Membrane transporters, among them the calmodulin (CaM)-activated plasma membrane Ca2+ ATPases (PMCAs) that extrude Ca2+ from the cell, play a key role in neuronal Ca2+ homeostasis. Using X-exome sequencing we have identified a missense mutation (G1107D) in the CaM-binding domain of isoform 3 of the PMCAs in a family with X-linked congenital cerebellar ataxia. PMCA3 is highly expressed in the cerebellum, particularly in the presynaptic terminals of parallel fibers-Purkinje neurons. To study the effects of the mutation on Ca2+ extrusion by the pump, model cells (HeLa) were cotransfected with expression plasmids encoding its mutant or wild-type (wt) variants and with the Ca2+-sensing probe aequorin. The mutation reduced the ability of the PMCA3 pump to control the cellular homeostasis of Ca2+. It significantly slowed the return to baseline of the Ca2+ transient induced by an inositol-trisphosphate (InsP3)-linked plasma membrane agonist. It also compromised the ability of the pump to oppose the influx of Ca2+ through the plasma membrane capacitative channels.

Original languageEnglish
Pages (from-to)14514-14519
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number36
DOIs
Publication statusPublished - Sep 4 2012

Keywords

  • Calcium dysregulation
  • Cerebellar atrophy
  • Isoforms
  • Plasma membrane calcium pumps
  • X-linked ataxia

ASJC Scopus subject areas

  • General

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