Reduced expression of the Ca<sup>2+</sup>transporter protein PMCA2 slows Ca<sup>2+</sup>dynamics in mouse cerebellar Purkinje neurones and alters the precision of motor coordination

Empson, Ruth M.; Turner, Paul; Nagaraja, Raghavendra Y.; Beesley, Philip; Knöpfel, Thomas

doi:10.1113/jphysiol.2009.182196

Cited by 38 publications

(32 citation statements)

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“…As mentioned above, reduced Ca 2+ influx has been reported in the PNs of an ataxic mouse (7,8) and has been claimed to exacerbate the severity of other ataxic models (29). An ataxic phenotype (see above) has also been induced by the ablation of the PMCA2 gene in mice (12). However, no gene defects of Ca 2+ ATPases (or of other Ca 2+ transporters) had been reported to date in human ataxias.…”

Section: Discussionmentioning

confidence: 93%

“…Deafness in the pmca2 KO mice has also been associated with an ataxic phenotype in which PNs show shrunken dendrites and reduced firing frequency attributable to a K + current driven by extraresidual Ca 2+ , which prevents the regeneration of the action potential. Basal Ca 2+ levels in these neurons are high, and the Ca 2+ recovery kinetics slow: reduced Ca 2+ clearance attributable to a PMCA pump defect perturbs Ca 2+ dynamics in PN dendrites and disrupts the accuracy of cerebellar processing and motor coordination (12).…”

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confidence: 99%

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Mutation of plasma membrane Ca ²⁺ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca ²⁺ homeostasis

Zanni

Calì

Kalscheuer

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

111

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Ca 2+ 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 Ca 2+ ATPases (PMCAs) that extrude Ca 2+ from the cell, play a key role in neuronal Ca 2+ 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 Ca 2+ extrusion by the pump, model cells (HeLa) were cotransfected with expression plasmids encoding its mutant or wild-type (wt) variants and with the Ca 2+ -sensing probe aequorin. The mutation reduced the ability of the PMCA3 pump to control the cellular homeostasis of Ca 2+ . It significantly slowed the return to baseline of the Ca 2+ transient induced by an inositol-trisphosphate (InsP 3 )-linked plasma membrane agonist. It also compromised the ability of the pump to oppose the influx of Ca 2+ through the plasma membrane capacitative channels.calcium dysregulation | plasma membrane calcium pumps | isoforms | X-linked ataxia | cerebellar atrophy T he tight regulation of cell Ca 2+ is crucial for neuronal development, function, and survival. The free Ca 2+ level of neurons at rest is four orders of magnitude lower than in the external medium. Ca 2+ coming from outside or from cellular stores regulates neuronal processes like excitability, neurotransmitter release, synaptic efficacy, and gene expression. The plasma membrane Ca 2+ ATPases (PMCAs) cooperate with the Na + /Ca 2+ exchangers of the plasma membrane (NCX), the endoplasmic reticulum (ER) Ca 2+ -ATPases (SERCA pumps), and the mitochondrial Ca 2+ uptake system in counteracting the transient Ca 2+ increases produced by neuronal stimulation by the influx of Ca 2+ through voltage-and ligand-gated plasma membrane channels, the ER inositol-trisphosphate receptor (InsP 3 R), and the ryanodine receptor (RyR) channels, and through the mitochondrial Ca 2+ release system(s) (1). PMCA isoforms in mammals are the products of 4 separate genes, and the number of variants is increased to over 30 by alternative splicing of mRNAs, which affects the first cytosolic loop of the pump (site A) and its C-terminal tail (site C). The splicing variants are cell-specific and undergo regulation during cell development and differentiation. PMCAs consist of 10 transmembrane domains, 2 large intracellular loops, and N-and C-terminal cytoplasmic tails. The C-terminal tail contains the regulatory calmodulin (CaM)-binding domain, which interacts with two sites in the two cytosolic loops of the pump autoinhibiting the pump at rest: CaM displaces the domain from the two sites restoring full pump activity (2, 3). PMCA1 and PMCA4 are expressed in most tissues, ...

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Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

Mutation of plasma membrane Ca ²⁺ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca ²⁺ homeostasis

Zanni

Calì

Kalscheuer

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

111

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“…The hereditary deafness caused by mutations of the PMCA2 isoform (7,9) can be associated with ataxic symptoms (10,11). An ataxia-causing defect was recently described in PMCA3 (12).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the deafness phenotype was not the only associated phenotype: one of the PMCA2-defective mice also had prominent ataxic symptoms (10). The PMCA2 knock-out mice exhibited ataxic phenotype, with cerebellar dysfunctions associated with shrunken Purkinje neurons dendrites and reduced firing frequency (11). As for PMCA3, a missense mutation of a residue in the C-terminal calmodulin-binding domain has been recently identified and studied in a family with X-linked congenital cerebellar ataxia associated with cerebellar atrophy (12).…”

Section: Camentioning

confidence: 99%

A Novel Mutation in Isoform 3 of the Plasma Membrane Ca2+ Pump Impairs Cellular Ca2+ Homeostasis in a Patient with Cerebellar Ataxia and Laminin Subunit 1α Mutations

Calì¹,

Lopreiato

Shimony

et al. 2015

Journal of Biological Chemistry

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Background: Mutations in plasma membrane Ca 2ϩ -ATPase (PMCA) isoform 3 and in laminin subunit 1␣ have previously been linked to ataxic phenotypes. Results: A novel PMCA3 missense mutation co-occurring with a compound heterozygous mutation in laminin subunit 1␣ impaired cellular Ca 2ϩ homeostasis. Conclusion:The two mutations could work synergistically to generate the disease phenotype. Significance: A digenic mechanism could be responsible for this case of cerebellar ataxia.

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“…Whilst these results indicated the importance of PMCA2 in the PN dendrites for adequate calcium control, a more quantitative approach was required. To do this, we took advantage of the PMCA2 +/-heterozygous mouse where the PNs were not visibly stunted or disordered, but where PMCA2 expression in the PNs was reduced to about half its wild type levels [34] (as also predicted from Northern analysis [18] ). Under these conditions the decay kinetics of CF-induced calcium transients are significantly slowed.…”

Section: +mentioning

confidence: 99%

Contribution of plasma membrane Ca²⁺ATPase to cerebellar synapse function

Huang

Nagaraja²,

Garside³

et al. 2010

WJBC

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The cerebellum expresses one of the highest levels of the plasma membrane Ca 2+ ATPase, isoform 2 in the mammalian brain. This highly efficient plasma membrane calcium transporter protein is enriched within the main output neurons of the cerebellar cortex; i.e. the Purkinje neurons (PNs). Here we review recent evidence, including electrophysiological and calcium imaging approaches using the plasma membrane calcium ATPase 2 (PMCA2) knockout mouse, to show that PMCA2 is critical for the physiological control of calcium at cerebellar synapses and cerebellar dependent behaviour. These studies have also revealed that deletion of PMCA2 throughout cerebellar development in the PMCA2 knockout mouse leads to permanent signalling and morphological alterations in the PN dendrites. Whilst these findings highlight the importance of PMCA2 during cerebellar synapse function and development, they also reveal some limitations in the use of the PMCA2 knockout mouse and the need for additional experimental approaches including cell-specific and reversible manipulation of PMCAs. THE CEREBELLUM, THE PURKINJE NEURON AND THE IMPORTANCE OF CALCIUM DYNAMICS AT CEREBELLAR SYNAPSESThe cerebellum is a major centre for the integration of sensory and motor information in the brain and plays a central role in our ability to learn and refine motor tasks; the specialised function of the cerebellum allows us to execute motor tasks in a finely controlled but, at the same time, "unaware" manner that can still be improved by learning. For a detailed review of cerebellar function TOPIC HIGHLIGHTWorld J Biol Chem 2010 May 26; 1(5): 95-102 ISSN 1949-8454 (online)

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Reduced expression of the Ca²⁺transporter protein PMCA2 slows Ca²⁺dynamics in mouse cerebellar Purkinje neurones and alters the precision of motor coordination

Abstract: +/− and wild-type mice, although PMCA2 +/− mice were always impaired. We conclude that reduced calcium clearance perturbs calcium dynamics in PN dendrites and that this is sufficient to disrupt the accuracy of cerebellar processing and motor coordination.

Cited by 38 publications

References 58 publications

Mutation of plasma membrane Ca ²⁺ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca ²⁺ homeostasis

Mutation of plasma membrane Ca ²⁺ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca ²⁺ homeostasis

A Novel Mutation in Isoform 3 of the Plasma Membrane Ca2+ Pump Impairs Cellular Ca2+ Homeostasis in a Patient with Cerebellar Ataxia and Laminin Subunit 1α Mutations

Contribution of plasma membrane Ca²⁺ATPase to cerebellar synapse function

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Reduced expression of the Ca2+transporter protein PMCA2 slows Ca2+dynamics in mouse cerebellar Purkinje neurones and alters the precision of motor coordination

Abstract: +/− and wild-type mice, although PMCA2 +/− mice were always impaired. We conclude that reduced calcium clearance perturbs calcium dynamics in PN dendrites and that this is sufficient to disrupt the accuracy of cerebellar processing and motor coordination.

Cited by 38 publications

References 58 publications

Mutation of plasma membrane Ca 2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca 2+ homeostasis

Mutation of plasma membrane Ca 2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca 2+ homeostasis

A Novel Mutation in Isoform 3 of the Plasma Membrane Ca2+ Pump Impairs Cellular Ca2+ Homeostasis in a Patient with Cerebellar Ataxia and Laminin Subunit 1α Mutations

Contribution of plasma membrane Ca2+ATPase to cerebellar synapse function

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Product

Resources

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Reduced expression of the Ca²⁺transporter protein PMCA2 slows Ca²⁺dynamics in mouse cerebellar Purkinje neurones and alters the precision of motor coordination

Mutation of plasma membrane Ca ²⁺ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca ²⁺ homeostasis

Mutation of plasma membrane Ca ²⁺ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca ²⁺ homeostasis

Contribution of plasma membrane Ca²⁺ATPase to cerebellar synapse function