The Homer-1 protein Ania-3 interacts with the plasma membrane calcium pump

Sgambato-Faure, Véronique; Xiong, Yuning; Berke, Joshua D.; Hyman, Steven E.; Strehler, Emanuel E.

doi:10.1016/j.bbrc.2006.03.020

Cited by 55 publications

(46 citation statements)

References 44 publications

(66 reference statements)

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“…The CASK syndrome is caused by the disruption of the gene for the Ca 2+ -CaM-dependent protein kinase, and it may be significant that CASK interacts through its PDZ [Post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and Zonula occludens-1 protein (zo-1)]-binding domain with the C terminal of the PMCA pump (41). PMCAs are part of a postsynaptic complex formed by metabotropic glutamate receptors (mGluR1), Homer (which interacts with OPHN1), and InsP 3 type 1 receptors (InsP 3 R1) (42)(43)(44). The levels of mGluR1 and InsP 3 R1 are reduced in PNs in several mouse models of ataxia, and it is interesting that late-onset human degenerative ataxias with a pure cerebellar phenotype have been related to the disruption of Ca 2+ -and InsP 3 R-dependent signaling pathways (45).…”

Section: Discussionmentioning

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.

110

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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: 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.

110

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“…The participation of several PMCA isoforms including PMCA4b in noncovalent multi-protein complexes is now well documented, and numerous interacting partners have been identified [70][71][72][73][74][75][76][77][78][79][80]. Several of these interactions result in the modulation by PMCA of the function or activity of the interacting partners and appear to be specific when compared to other PMCA isoforms.…”

Section: Discussionmentioning

confidence: 99%

Isoform-specific up-regulation of plasma membrane Ca2+ATPase expression during colon and gastric cancer cell differentiation

Ribiczey¹,

Tordai²,

Andrikovics³

et al. 2007

Cell Calcium

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SummaryIn this work we demonstrate a differentiation-induced up-regulation of the expression of plasma membrane Ca 2+ ATPase (PMCA) isoforms being present in various gastric/colon cancer cell types. We found PMCA1b as the major isoform in non-differentiated cancer cell lines, whereas the expression level of PMCA4b was significantly lower. Cell differentiation initiated with short chain fatty acids (SCFAs) and trichostatin A, or spontaneous differentiation of post-confluent cell cultures resulted in a marked induction of PMCA4b expression, while only moderately increased PMCA1b levels. Up-regulation of PMCA4b expression was demonstrated both at the protein and mRNA levels, and closely correlated with the induction of established differentiation markers. In contrast, the expression level of the Na + /K + -ATPase or that of the sarco/endoplasmic reticulum Ca 2+ ATPase 2 protein did not change significantly under these conditions. In membrane vesicles obtained from SCFA-treated gastric/colon cancer cells a marked increase in the PMCA-dependent Ca 2+ transport activity was observed, indicating a general increase of PMCA function during the differentiation of these cancer cells.Because various PMCA isoforms display distinct functional characteristics, we suggest that upregulated PMCA expression, together with a major switch in PMCA isoform pattern may significantly contribute to the differentiation of gastric/colon cancer cells. The analysis of PMCA expression may provide a new diagnostic tool for monitoring the tumor phenotype.

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“…This is especially pertinent given the critical role of the PMCAs in maintaining neuronal [Ca 2+ ]i and also its newly assigned role in modulating cellular signaling pathways [69] . The PMCAs have been shown to interact with a number of signaling proteins such as nNOS, calcineurin, and various members of the membrane microdomain organizing proteins of the membrane-associated guanylate kinase family [70][71][72][73][74][75][76][77] . More recently, the PMCAs have been shown to be localized in neuronal lipid rafts, cholesterol-enriched microdomains in the plasma membrane [78,79] , believed to be local centers for cell signaling events.…”

Section: Pmca Expressionmentioning

confidence: 99%

“…The PMCAs have been found to be significantly downregulated in models of global ischemia-reperfusion injury and seizures [65,[73][74][75][76][77] . Evidence suggests that the suppression of PMCA activity is not simply due to the disruption of ion gradients and lowered ATP levels associated with these conditions, but rather due to oxidative modification and degradation of the PMCA protein [96] .…”

Section: The Pmcas and Neurodegenerationmentioning

confidence: 99%

Plasma membrane Ca²⁺-ATPases: Targets of oxidative stress in brain aging and neurodegeneration

Zaidi¹

2010

WJBC

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The plasma membrane Ca 2+ -ATPase (PMCA) pumps play an important role in the maintenance of precise levels of intracellular Ca 2+ [Ca 2+ ]i, essential to the functioning of neurons. In this article, we review evidence showing age-related changes of the PMCAs in synaptic plasma membranes (SPMs). PMCA activity and protein levels in SPMs diminish progressively with increasing age. The PMCAs are very sensitive to oxidative stress and undergo functional and structural changes when exposed to oxidants of physiological relevance. The major signatures of oxidative modification in the PMCAs are rapid inactivation, conformational changes, aggregation, internalization from the plasma membrane and proteolytic degradation. PMCA proteolysis appears to be mediated by both calpains and caspases. The predominance of one proteolytic pathway vs the other, the ensuing pattern of PMCA degradation and its consequence on pump activity depends largely on the type of insult, its intensity and duration. Experimental reduction of PMCA expression not only alters the dynamics of cellular Ca 2+ handling but also has a myriad of downstream consequences on various aspects of cell function, indicating a broad role of these pumps. Age-and oxidation-related down-regulation of the PMCAs may play an important role in compromised neuronal function in the aging brain and its several-fold increased susceptibility to neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and stroke. Therapeutic approaches that protect the PMCAs and stabilize [Ca 2+ ]i homeostasis may be capable of slowing and/or preventing neuronal degeneration. The PMCAs are therefore emerging as a new class of drug targets for therapeutic interventions in various chronic degenerative disorders.

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The Homer-1 protein Ania-3 interacts with the plasma membrane calcium pump

Cited by 55 publications

References 44 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

Isoform-specific up-regulation of plasma membrane Ca2+ATPase expression during colon and gastric cancer cell differentiation

Plasma membrane Ca²⁺-ATPases: Targets of oxidative stress in brain aging and neurodegeneration

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The Homer-1 protein Ania-3 interacts with the plasma membrane calcium pump

Cited by 55 publications

References 44 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

Isoform-specific up-regulation of plasma membrane Ca2+ATPase expression during colon and gastric cancer cell differentiation

Plasma membrane Ca2+-ATPases: Targets of oxidative stress in brain aging and neurodegeneration

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Product

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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

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

Plasma membrane Ca²⁺-ATPases: Targets of oxidative stress in brain aging and neurodegeneration