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Dive into the research topics where Malwina Lisek is active.

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Featured researches published by Malwina Lisek.


Cell Calcium | 2012

Downregulation of PMCA2 or PMCA3 reorganizes Ca2+ handling systems in differentiating PC12 cells

Tomasz Boczek; Malwina Lisek; Antoni Kowalski; Slawomir Pikula; Jolanta Niewiarowska; Magdalena Wiktorska; Ludmila Zylinska

Changes in PMCA2 and PMCA3 expression during neuronal development are tightly linked to structural and functional modifications in Ca(2+) handling machinery. Using antisense strategy we obtained stably transfected PC12 lines with reduced level of PMCA2 or PMCA3, which were then subjected to dibutyryl-cAMP differentiation. Reduced level of neuron-specific PMCAs led to acceleration of differentiation and formation of longer neurites than in control PC12 line. Treatment with dibutyryl-cAMP was associated with retraction of growth cones and intensified formation of varicosities. In PMCA2-reduced cells development of apoptosis and DNA laddering were detected. Higher amounts of constitutive isoforms PMCA1 and PMCA4, their putative extended location to gaps left after partial removal of PMCA2 or PMCA3, together with increased SERCA may indicate the induction of compensatory mechanism in modified cells. Functional studies showed altered expression of certain types of VDCCs in PMCA-reduced cells, which correlated with their higher contribution to Ca(2+) influx. The cell response to PMCAs suppression suggests the interplay between transcription level of two opposite calcium-transporting systems i.e. voltage- and store depletion-activated channels facilitating Ca(2+) influx and calcium pumps responsible for Ca(2+) clearance, as well highlights the role of both neuron-specific PMCA isoforms in the control of PC12 cells differentiation.


PLOS ONE | 2014

Plasma Membrane Ca2+-ATPase Isoforms Composition Regulates Cellular pH Homeostasis in Differentiating PC12 Cells in a Manner Dependent on Cytosolic Ca2+ Elevations

Tomasz Boczek; Malwina Lisek; Bozena Ferenc; Antoni Kowalski; Dariusz Stepinski; Magdalena Wiktorska; Ludmila Zylinska

Plasma membrane Ca2+-ATPase (PMCA) by extruding Ca2+ outside the cell, actively participates in the regulation of intracellular Ca2+ concentration. Acting as Ca2+/H+ counter-transporter, PMCA transports large quantities of protons which may affect organellar pH homeostasis. PMCA exists in four isoforms (PMCA1-4) but only PMCA2 and PMCA3, due to their unique localization and features, perform more specialized function. Using differentiated PC12 cells we assessed the role of PMCA2 and PMCA3 in the regulation of intracellular pH in steady-state conditions and during Ca2+ overload evoked by 59 mM KCl. We observed that manipulation in PMCA expression elevated pHmito and pHcyto but only in PMCA2-downregulated cells higher mitochondrial pH gradient (ΔpH) was found in steady-state conditions. Our data also demonstrated that PMCA2 or PMCA3 knock-down delayed Ca2+ clearance and partially attenuated cellular acidification during KCl-stimulated Ca2+ influx. Because SERCA and NCX modulated cellular pH response in neglectable manner, and all conditions used to inhibit PMCA prevented KCl-induced pH drop, we considered PMCA2 and PMCA3 as mainly responsible for transport of protons to intracellular milieu. In steady-state conditions, higher TMRE uptake in PMCA2-knockdown line was driven by plasma membrane potential (Ψp). Nonetheless, mitochondrial membrane potential (Ψm) in this line was dissipated during Ca2+ overload. Cyclosporin and bongkrekic acid prevented Ψm loss suggesting the involvement of Ca2+-driven opening of mitochondrial permeability transition pore as putative underlying mechanism. The findings presented here demonstrate a crucial role of PMCA2 and PMCA3 in regulation of cellular pH and indicate PMCA membrane composition important for preservation of electrochemical gradient.


Cell and Tissue Research | 2016

Regional brain dysregulation of Ca2+-handling systems in ketamine-induced rat model of experimental psychosis

Malwina Lisek; Tomasz Boczek; Bozena Ferenc; Ludmila Zylinska

Chronic N-methyl-D-aspartate receptor (NMDAR) antagonist treatment can provide valuable neurochemical and neuroanatomical models of experimental psychosis. One such antagonist, ketamine, with its short half-time and well-documented psychotomimetic action, has cognitive effects resembling various aspects of schizophrenia-like symptoms. In order to obtain insights into possible relationships between Ca2+ homeostasis and schizophrenia-related symptoms, we investigate the effects of chronic ketamine administration on intracellular Ca2+ levels in various brain regions and on the expression level of key members of the neuronal Ca2+-handling system in rats. We show increased intracellular [Ca2+] in all of the examined brain regions following ketamine treatment but an altered cytosolic Ca2+ level correlated with hyperlocomotor activity was only established for the cortex and striatum. Our findings also suggest that an imbalance in the expression between the calcium “on” and “off” systems contributes to the deregulation of brain Ca2+ homeostasis in our ketamine-induced model of experimental psychosis. Identification of the genes whose expression is affected by ketamine treatment indicates their involvement as putative etiological factors in schizophrenia.


BioMed Research International | 2014

Silencing of plasma membrane Ca2+-ATPase isoforms 2 and 3 impairs energy metabolism in differentiating PC12 cells.

Tomasz Boczek; Malwina Lisek; Bozena Ferenc; Antoni Kowalski; Magdalena Wiktorska; Ludmila Zylinska

A close link between Ca2+, ATP level, and neurogenesis is apparent; however, the molecular mechanisms of this relationship have not been completely elucidated. Transient elevations of cytosolic Ca2+ may boost ATP synthesis, but ATP is also consumed by ion pumps to maintain a low Ca2+ in cytosol. In differentiation process plasma membrane Ca2+ ATPase (PMCA) is considered as one of the major players for Ca2+ homeostasis. From four PMCA isoforms, the fastest PMCA2 and PMCA3 are expressed predominantly in excitable cells. In the present study we assessed whether PMCA isoform composition may affect energy balance in differentiating PC12 cells. We found that PMCA2-downregulated cells showed higher basal O2 consumption, lower NAD(P)H level, and increased activity of ETC. These changes associated with higher [Ca2+]c resulted in elevated ATP level. Since PMCA2-reduced cells demonstrated greatest sensitivity to ETC inhibition, we suppose that the main source of energy for PMCA isoforms 1, 3, and 4 was oxidative phosphorylation. Contrary, cells with unchanged PMCA2 expression exhibited prevalence of glycolysis in ATP generation. Our results with PMCA2- or PMCA3-downregulated lines provide an evidence of a novel role of PMCA isoforms in regulation of bioenergetic pathways, and mitochondrial activity and maintenance of ATP level during PC12 cells differentiation.


Frontiers in Cellular Neuroscience | 2017

Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction

Malwina Lisek; Bozena Ferenc; Maciej Studzian; Lukasz Pulaski; Feng Guo; Ludmila Zylinska; Tomasz Boczek

Ketamine causes psychotic episodes and is often used as pharmacological model of psychotic-like behavior in animals. There is increasing evidence that molecular mechanism of its action is more complicated than just N-methyl-D-aspartic acid (NMDA) receptor antagonism and involves interaction with the components of calcium homeostatic machinery, in particular plasma membrane calcium pump (PMCA). Therefore, in this study we aimed to characterize brain region-specific effects of ketamine on PMCA activity, interaction with NMDA receptor through postsynaptic density protein 95 (PSD95) scaffolding proteins and glutamate release from nerve endings. In our study, ketamine induced behavioral changes in healthy male rats consistent with psychotic effects. In the same animals, we were able to demonstrate significant inhibition of plasma membrane calcium ATPase (PMCA) activity in cerebellum, hippocampus and striatum. The expression level and isoform composition of PMCAs were also affected in some of these brain compartments, with possible compensatory effects of PMCA1 substituting for decreased expression of PMCA3. Expression of the PDZ domain-containing scaffold protein PSD95 was induced and its association with PMCA4 was higher in most brain compartments upon ketamine treatment. Moreover, increased PSD95/NMDA receptor direct interaction was also reported, strongly suggesting the formation of multiprotein complexes potentially mediating the effect of ketamine on calcium signaling. We further support this molecular mechanism by showing brain region-specific changes in PSD95/PMCA4 spatial colocalization. We also show that ketamine significantly increases synaptic glutamate release in cortex and striatum (without affecting total tissue glutamate content), inducing the expression of vesicular glutamate transporters and decreasing the expression of membrane glutamate reuptake pump excitatory amino acid transporters 2 (EAAT2). Thus, ketamine-mediated PMCA inhibition, by decreasing total Ca2+ clearing potency, may locally raise cytosolic Ca2+ promoting excessive glutamate release. Regional alterations in glutamate secretion can be further driven by PSD95-mediated spatial recruitment of signaling complexes including glutamate receptors and calcium pumps, representing a novel mechanism of psychogenic action of ketamine.


Neurochemistry International | 2015

Region-specific effects of repeated ketamine administration on the presynaptic GABAergic neurochemistry in rat brain.

Tomasz Boczek; Malwina Lisek; Bozena Ferenc; Magdalena Wiktorska; Ivana Ivchevska; Ludmila Zylinska

A growing body of evidence indicates that clinical use of ketamine as a promising antidepressant can be accompanied by psychotic-like side effects. Although, the generation of such effects is thought to be attributed to dysfunction of prefrontal GABAergic interneurons, the mechanism underlying ketamines propsychotic-like action is not fully understood. Due to wide spectrum of behavioral abnormalities, it is hypothesized that ketamine action is not limited to only cortical GABA metabolism but may also involve alterations in other functional brain areas. To test it, we treated rats with ketamine (30 mg/kg, i.p.) for 5 days, and next we analyzed GABA metabolizing enzymes in cortex, cerebellum, hippocampus and striatum. Our results demonstrated that diminished GAD67 expression in cortex, cerebellum (by ∼60%) and in hippocampus (by ∼40%) correlated with lowered protein level in these areas. The expression of GAD65 isoform decreased by ∼45% in striatum, but pronounced increase by ∼90% was observed in hippocampus. Consecutively, reduction in glutamate decarboxylase activity and GABA concentration were detected in cortex, cerebellum and striatum, but not in hippocampus. Ketamine administration decreased GABA transaminase protein in cortex and striatum (by ∼50% and 30%, respectively), which was reflected in diminished activity of the enzyme. Also, a significant drop in succinic semialdehyde dehydrogenase activity in cortex, cerebellum and striatum was present. These data suggest a reduced utilization of GABA for energetic purposes. In addition, we observed synaptic GABA release to be reduced by ∼30% from striatal terminals. It correlated with lowered KCl-induced Ca(2+) influx and decreased amount of L-type voltage-dependent calcium channel. Our results indicate that unique changes in GABA metabolism triggered by chronic ketamine treatment in functionally distinct brain regions may be involved in propsychotic-like effects of this drug.


Biochimica et Biophysica Acta | 2017

Cross talk among PMCA, calcineurin and NFAT transcription factors in control of calmodulin gene expression in differentiating PC12 cells

Tomasz Boczek; Malwina Lisek; Bozena Ferenc; Ludmila Zylinska

Brain aging is characterized by progressive loss of plasma membrane calcium pump (PMCA) and its activator - calmodulin (CaM), but the mechanism of this phenomenon remains unresolved. CaM encoded by three genes Calm1, Calm2, Calm3, works to translate Ca2+ signal into changes in frequently opposite cellular activities. This unique function allows CaM to affect gene expression via stimulation of calcineurin (CaN) and its downstream target - nuclear factor of activated T-cells (NFAT) and to terminate Ca2+ signal by stimulation of its extrusion. PMCA, which exists in four isoforms PMCA1-4, may in turn shape the pattern of Ca2+ transients and control CaN activity by its direct binding. Therefore, the interplay between PMCA, CaM and CaN/NFAT is highly plausible. To verify that, we used differentiated PC12 cells with reduced expression of PMCA2 or PMCA3 to mimic the potential changes in aged brain. Manipulation in PMCAs level decreased CaM protein in PMCA2 or PMCA3-reduced lines that was accompanied by down-regulation of Calm1 and Calm2 in both lines, but Calm3 only in PMCA2-reduced cells. Further studies showed substantially higher NFATc2 nuclear accumulation and increased NFAT transcriptional activity. Blocking of CaN/NFAT signalling resulted in almost full CaM recovery, mainly due to up-regulation of Calm2 and Calm3 genes. Moreover, higher occupancy of Calm2 and Calm3 promoters by NFATc2 and increased expression of these genes in response to NFATc2 silencing were demonstrated in PMCA2 and PMCA3-reduced lines. Our results indicate that decrease in CaM level in response to PMCAs downregulation can be driven by CaN/NFAT pathway.


Neuroscience Letters | 2017

Calcium as a Trojan horse in mental diseases—The role of PMCA and PMCA-interacting proteins in bipolar disorder and schizophrenia

Malwina Lisek; Tomasz Boczek; Ludmila Zylinska

Although first mentions about calcium disturbances in psychiatric diseases appeared more than 30 years ago, the most recent genomic and proteomic findings confirmed a significant role of Ca2+ and Ca2+-regulated pathways in development of neuropathological processes, including bipolar disorder and schizophrenia. Moreover, last decades have shown that due to multifactorial nature of both diseases, impairment in neuronal calcium homeostasis may depend not only on disturbed Ca2+ entry system, but also on altered extrusion system. A pivotal role in Ca2+ clearance mechanism is played by plasma membrane Ca2+-ATPase (PMCA), the enzyme responsible for returning the elevated levels of cytosolic Ca2+ back to the resting state. In this paper we summarize the current knowledge about the role of PMCA in bipolar disorder and schizophrenia pathologies, as well as the contribution of several proteins that by interaction with PMCA modify signal transduction mechanisms.


Molecular and Cellular Biochemistry | 2015

Regulation of GAP43/calmodulin complex formation via calcineurin-dependent mechanism in differentiated PC12 cells with altered PMCA isoforms composition

Tomasz Boczek; Bozena Ferenc; Malwina Lisek; Ludmila Zylinska


Biochemical and Biophysical Research Communications | 2015

Plasma membrane Ca(2+)-ATPase is a novel target for ketamine action.

Tomasz Boczek; Malwina Lisek; Bozena Ferenc; Ludmila Zylinska

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Ludmila Zylinska

Medical University of Łódź

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Tomasz Boczek

Medical University of Łódź

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Bozena Ferenc

Medical University of Łódź

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Antoni Kowalski

Medical University of Łódź

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Magdalena Wiktorska

Medical University of Łódź

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Elżbieta Rębas

Medical University of Łódź

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Jolanta Niewiarowska

Medical University of Łódź

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