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

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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.

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Zanni, G., Calì, T., Kalscheuer, V. M., Ottolini, D., Barresi, S., Lebrun, N., … Carafoli, E. (2012). Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 109(36), 14514–14519. https://doi.org/10.1073/pnas.1207488109

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