Interaction of plasma membrane Ca2+-ATPase isoform 4 with calcineurin A: Implications for catecholamine secretion by PC12 cells

Kosiorek, Michalina; Podszywałow-Bartnicka, Paulina; Żylińska, Ludmiła; Zabłocki, Krzysztof; Pikula, Sławomir

doi:10.1016/j.bbrc.2011.06.098

Cited by 16 publications

(19 citation statements)

References 32 publications

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“…Thus, we used an in vitro cellular model with permanently downregulated PMCA2 and PMCA3 expression, which was validated in our several other studies [58]–[60]. At this point a comment should be added why the RNAi method was not appropriate regarding assumptions of this research.…”

Section: Resultsmentioning

confidence: 93%

“…In some experiments the inhibitor of NFAT (1 µM 11R-VIVIT) (Calbiochem Merck Chemicals, Germany) was added for 48 h to the cell culture. Cell lines deficient in PMCA2 (_2) or PMCA3 (_3) were established as described previously [59], [60]. Control cells (C) were transfected with empty pcDNA3.1 (+) plasmid.…”

Section: Methodsmentioning

confidence: 99%

“…The protein content was determined by the Bradford assay. Total cell lysates were analyzed by SDS-PAGE and immunoblotting as described [60] using the antibodies described in table 2 (Table 2 and Table S1). …”

Section: Methodsmentioning

confidence: 99%

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NFAT1 and NFAT3 Cooperate with HDAC4 during Regulation of Alternative Splicing of PMCA Isoforms in PC12 Cells

Kosiorek

Podszywałow-Bartnicka

Żylińska

et al. 2014

PLoS ONE

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BackgroundThe bulk of human genes undergo alternative splicing (AS) upon response to physiological stimuli. AS is a great source of protein diversity and biological processes and is associated with the development of many diseases. Pheochromocytoma is a neuroendocrine tumor, characterized by an excessive Ca2+-dependent secretion of catecholamines. This underlines the importance of balanced control of calcium transport via regulation of gene expression pattern, including different calcium transport systems, such as plasma membrane Ca2+-ATPases (PMCAs), abundantly expressed in pheochromocytoma chromaffin cells (PC12 cells). PMCAs are encoded by four genes (Atp2b1, Atp2b2, Atp2b3, Atp2b4), whose transcript products undergo alternative splicing giving almost 30 variants.ResultsIn this scientific report, we propose a novel mechanism of regulation of PMCA alternative splicing in PC12 cells through cooperation of the nuclear factor of activated T-cells (NFAT) and histone deacetylases (HDACs). Luciferase assays showed increased activity of NFAT in PC12 cells, which was associated with altered expression of PMCA. RT-PCR experiments suggested that inhibition of the transcriptional activity of NFAT might result in the rearrangement of PMCA splicing variants in PC12 cells. NFAT inhibition led to dominant expression of 2x/c, 3x/a and 4x/a PMCA variants, while in untreated cells the 2w,z/b, 3z,x/b,c,e,f, and 4x/b variants were found as well. Furthermore, chromatin immunoprecipitation experiments showed that NFAT1-HDAC4 or NFAT3-HDAC4 complexes might be involved in regulation of PMCA2x splicing variant generation.ConclusionsWe suggest that the influence of NFAT/HDAC on PMCA isoform composition might be important for altered dopamine secretion by PC12 cells.

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Section: Resultsmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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NFAT1 and NFAT3 Cooperate with HDAC4 during Regulation of Alternative Splicing of PMCA Isoforms in PC12 Cells

Kosiorek

Podszywałow-Bartnicka

Żylińska

et al. 2014

PLoS ONE

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“…The interaction was first witnessed in PMCA4 overexpressing HEK cells and mapped to the catalytic subunit of calcineurin A, with consequential attenuation of calcineurinnuclear factor of activated T cells (NFAT) signaling (46). Calcineurin has since been noted to also interact with PMCA2 and 4 in breast cancer cells and PMCA1, 2, and 4 in endothelial cells (158,159), as well as with PMCA4 in the PC12 pheochromocytoma cell line (189). Calcineurin-NFAT signaling is one of the best characterized pathways in the development of pathological hypertrophy and remodeling (248), and thus this has prompted research into the function of this interaction during the hypertrophic process.…”

Section: Pmca and The Heartmentioning

confidence: 99%

The Plasma Membrane Calcium ATPasesand Their Role as Major New Players in Human Disease

Stafford

Wilson

Oceandy

et al. 2017

Physiological Reviews

110

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The Ca2+ extrusion function of the four mammalian isoforms of the plasma membrane calcium ATPases (PMCAs) is well established. There is also ever-increasing detail known of their roles in global and local Ca2+ homeostasis and intracellular Ca2+ signaling in a wide variety of cell types and tissues. It is becoming clear that the spatiotemporal patterns of expression of the PMCAs and the fact that their abundances and relative expression levels vary from cell type to cell type both reflect and impact on their specific functions in these cells. Over recent years it has become increasingly apparent that these genes have potentially significant roles in human health and disease, with PMCAs1-4 being associated with cardiovascular diseases, deafness, autism, ataxia, adenoma, and malarial resistance. This review will bring together evidence of the variety of tissue-specific functions of PMCAs and will highlight the roles these genes play in regulating normal physiological functions and the considerable impact the genes have on human disease.

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“…Previously, we demonstrated that the activity of Ca 2+ -dependent phosphatase, calcineurin, increased in PC12 cells as a consequence of downregulation of PMCA2 and PMCA3 isoforms [15]. One of the main substrates of calcineurin is the transcriptional nuclear factor of activated T-cells (NFAT).…”

Section: Introductionmentioning

confidence: 99%

Calcineurin/NFAT Signaling Represses Genes Vamp1 and Vamp2 via PMCA-Dependent Mechanism during Dopamine Secretion by Pheochromocytoma Cells

et al. 2014

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BackgroundPlasma membrane Ca2+-ATPases (PMCA) extrude Ca2+ ions out of the cell and contribute to generation of calcium oscillations. Calcium signaling is crucial for transcriptional regulation of dopamine secretion by neuroendocrine PC12 cells. Low resting [Ca2+]c in PC12 cells is maintained mainly by two Ca2+-ATPases, PMCA2 and PMCA3. Recently, we found that Ca2+ dependent phosphatase calcineurin was excessively activated under conditions of experimental downregulation of PMCA2 or PMCA3. Thus, the aim of this study was to explain if, via modulation of the Ca2+/calcineurin-dependent nuclear factor of activated T cells (NFAT) pathway, PMCA2 and PMCA3 affect intracellular signaling in pheochromocytoma/neuronal cells/PC12 cells. Secondly, we tested whether this might influence dopamine secretion by PC12 cells.ResultsPMCA2- and PMCA3-deficient cells displayed profound decrease in dopamine secretion accompanied by a permanent increase in [Ca2+]c. Reduction in secretion might result from changes in NFAT signaling, following altered PMCA pattern. Consequently, activation of NFAT1 and NFAT3 transcription factors was observed in PMCA2- or PMCA3-deficient cells. Furthermore, chromatin immunoprecipitation assay indicated that NFATs could be involved in repression of Vamp genes encoding vesicle associated membrane proteins (VAMP).ConclusionsPMCA2 and PMCA3 are crucial for dopamine secretion in PC12 cells. Reduction in PMCA2 or PMCA3 led to calcium-dependent activation of calcineurin/NFAT signaling and, in consequence, to repression of the Vamp gene and deterioration of the SNARE complex formation in PC12 cells.

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Interaction of plasma membrane Ca2+-ATPase isoform 4 with calcineurin A: Implications for catecholamine secretion by PC12 cells

Cited by 16 publications

References 32 publications

NFAT1 and NFAT3 Cooperate with HDAC4 during Regulation of Alternative Splicing of PMCA Isoforms in PC12 Cells

NFAT1 and NFAT3 Cooperate with HDAC4 during Regulation of Alternative Splicing of PMCA Isoforms in PC12 Cells

The Plasma Membrane Calcium ATPasesand Their Role as Major New Players in Human Disease

Calcineurin/NFAT Signaling Represses Genes Vamp1 and Vamp2 via PMCA-Dependent Mechanism during Dopamine Secretion by Pheochromocytoma Cells

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