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

73 Citations (Scopus)

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

Fingerprint

Cerebellar Ataxia
Calcium-Transporting ATPases
Protein Isoforms
Homeostasis
Cell Membrane
Mutation
Calmodulin
Aequorin
Exome
Membrane Transport Proteins
Purkinje Cells
Presynaptic Terminals
Inositol
Missense Mutation
Ion Channels
HeLa Cells
Synaptic Transmission
Neurodegenerative Diseases
Cerebellum
Plasmids

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. / Zanni, Ginevra; Calì, Tito; Kalscheuer, Vera M.; Ottolini, Denis; Barresi, Sabina; Lebrun, Nicolas; Montecchi-Palazzi, Luisa; Hu, Hao; Chelly, Jamel; Bertini, Enrico; Brini, Marisa; Carafoli, Ernesto.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 36, 04.09.2012, p. 14514-14519.

Research output: Contribution to journalArticle

Zanni, Ginevra ; Calì, Tito ; Kalscheuer, Vera M. ; Ottolini, Denis ; Barresi, Sabina ; Lebrun, Nicolas ; Montecchi-Palazzi, Luisa ; Hu, Hao ; Chelly, Jamel ; Bertini, Enrico ; Brini, Marisa ; Carafoli, Ernesto. / Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 36. pp. 14514-14519.
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AU - Ottolini, Denis

AU - Barresi, Sabina

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AU - Montecchi-Palazzi, Luisa

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AU - Carafoli, Ernesto

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AB - 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.

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