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Dive into the research topics where Martin Kolisek is active.

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Featured researches published by Martin Kolisek.


The FASEB Journal | 2006

Nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose regulate TRPM2 channels in T lymphocytes

Andreas Beck; Martin Kolisek; Leigh Anne Bagley; Andrea Fleig; Reinhold Penner

TRPM2 (previously designated TRPC7 or LTRPC2) is a Ca2+‐permeable nonselective cation channel that contains a C‐terminal enzymatic domain with pyrophosphatase activity, which specifically binds ADP‐ribose. Cyclic ADP‐ribose (cADPR) and hydrogen peroxide (H2O2) can facilitate ADPR‐mediated activation of heterologously expressed TRPM2. Here, we show that the two Ca2+‐mobilizing second messengers cyclic ADP‐ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) strongly activate natively expressed TRPM2 channels in Jurkat T cells. TRPM2 activation by both agonists can be partially suppressed by the ADPR antagonist adenosine monophosphate (AMP), which suggests that cADPR and NAADP lead to mobilization of endogenous ADPR presumably via metabolic conversion. The remaining channel activity is due to direct gating of TRPM2 by the two agonists and can be completely suppressed by 8‐Br‐cADPR, which suggests that cADPR and NAADP share a common binding site on TRPM2 that can regulate TRPM2 activity in synergy with ADPR. We conclude that cADPR and NAADP, in combination with ADPR, represent physiological co‐activators of TRPM2 that contribute to Ca2+ influx in T lymphocytes and presumably other cell types that express this channel.—Beck, A., Kolisek, M., Bagley, L. A., Fleig, A., Penner, R. Nicotinic acid adenine dinucleotide phosphate and cyclic ADP‐ribose regulate TRPM2 channels in T lymphocytes. FASEB J. 20, E47‐E54 (2006)


Journal of Biological Chemistry | 2008

SLC41A1 Is a Novel Mammalian Mg2+ Carrier

Martin Kolisek; Pierre Launay; Andreas Beck; Gerhard Sponder; Nicolas Serafini; Marcel Brenkus; Elisabeth M. Froschauer; Holger Martens; Andrea Fleig; Monika Schweigel

The molecular biology of mammalian magnesium transporters and their interrelations in cellular magnesium homeostasis are largely unknown. Recently, the mouse SLC41A1 protein was suggested to be a candidate magnesium transporter with channel-like properties when overexpressed in Xenopus laevis oocytes. Here, we demonstrate that human SLC41A1 overexpressed in HEK293 cells forms protein complexes and locates to the plasma membrane without, however, giving rise to any detectable magnesium currents during whole cell patch clamp experiments. Nevertheless, in a strain of Salmonella enterica exhibiting disruption of all three distinct magnesium transport systems (CorA, MgtA, and MgtB), overexpression of human SLC41A1 functionally substitutes these transporters and restores the growth of the mutant bacteria at magnesium concentrations otherwise non-permissive for growth. Thus, we have identified human SLC41A1 as being a bona fide magnesium transporter. Most importantly, overexpressed SLC41A1 provide HEK293 cells with an increased magnesium efflux capacity. With outwardly directed Mg2+ gradients, a SLC41A1-dependent reduction of the free intracellular magnesium concentration accompanied by a significant net decrease of the total cellular magnesium concentration could be observed in such cells. SLC41A1 activity is temperature-sensitive but not sensitive to the only known magnesium channel blocker, cobalt(III) hexaammine. Taken together, these data functionally identify SLC41A1 as a mammalian carrier mediating magnesium efflux.


American Journal of Physiology-cell Physiology | 2012

Human gene SLC41A1 encodes for the Na+/Mg2+ exchanger

Martin Kolisek; Axel Nestler; Jürgen Vormann; Monika Schweigel-Röntgen

Magnesium (Mg(2+)), the second most abundant divalent intracellular cation, is involved in the vast majority of intracellular processes, including the synthesis of nucleic acids, proteins, and energy metabolism. The concentration of intracellular free Mg(2+) ([Mg(2+)](i)) in mammalian cells is therefore tightly regulated to its optimum, mainly by an exchange of intracellular Mg(2+) for extracellular Na(+). Despite the importance of this process for cellular Mg(2+) homeostasis, the gene(s) encoding for the functional Na(+)/Mg(2+) exchanger is (are) still unknown. Here, using the fluorescent probe mag-fura 2 to measure [Mg(2+)](i) changes, we examine Mg(2+) extrusion from hSLC41A1-overexpressing human embryonic kidney (HEK)-293 cells. A three- to fourfold elevation of [Mg(2+)](i) was accompanied by a five- to ninefold increase of Mg(2+) efflux. The latter was strictly dependent on extracellular Na(+) and reduced by 91% after complete replacement of Na(+) with N-methyl-d-glucamine. Imipramine and quinidine, known unspecific Na(+)/Mg(2+) exchanger inhibitors, led to a strong 88% to 100% inhibition of hSLC41A1-related Mg(2+) extrusion. In addition, our data show regulation of the transport activity via phosphorylation by cAMP-dependent protein kinase A. As these are the typical characteristics of a Na(+)/Mg(2+) exchanger, we conclude that the human SLC41A1 gene encodes for the Na(+)/Mg(2+) exchanger, the predominant Mg(2+) efflux system. Based on this finding, the analysis of Na(+)/Mg(2+) exchanger regulation and its involvement in the pathogenesis of diseases such as Parkinsons disease and hypertension at the molecular level should now be possible.


PLOS ONE | 2013

Substitution p.A350V in Na+/Mg2+ Exchanger SLC41A1, Potentially Associated with Parkinson's Disease, Is a Gain-of-Function Mutation

Martin Kolisek; Gerhard Sponder; Lucia Mastrototaro; Alina Smorodchenko; Pierre Launay; Juergen Vormann; Monika Schweigel-Röntgen

Parkinsons disease (PD) is a complex multifactorial ailment predetermined by the interplay of various environmental and genetic factors. Systemic and intracellular magnesium (Mg) deficiency has long been suspected to contribute to the development and progress of PD and other neurodegenerative diseases. However, the molecular background is unknown. Interestingly, gene SLC41A1 located in the novel PD locus PARK16 has recently been identified as being a Na+/Mg2+ exchanger (NME, Mg2+ efflux system), a key component of cellular magnesium homeostasis. Here, we demonstrate that the substitution p.A350V potentially associated with PD is a gain-of-function mutation that enhances a core function of SLC41A1, namely Na+-dependent Mg2+ efflux by 69±10% under our experimental conditions (10-minute incubation in high-Na+ (145 mM) and completely Mg2+-free medium). The increased efflux capacity is accompanied by an insensitivity of mutant NME to cAMP stimulation suggesting disturbed hormonal regulation and leads to a reduced proliferation rate in p.A350V compared with wt cells. We hypothesize that enhanced Mg2+-efflux conducted by SLC41A1 variant p.A350V might result, in the long-term, in chronic intracellular Mg2+-deficiency, a condition that is found in various brain regions of PD patients and that exacerbates processes triggering neuronal damage.


Magnesium Research | 2010

Splice-variant 1 of the ancient domain protein 2 (ACDP2) complements the magnesium-deficient growth phenotype of Salmonella enterica sv. typhimurium strain MM281

Gerhard Sponder; Sona Svidova; Monika Schweigel; Jürgen Vormann; Martin Kolisek

Evidence arguing for the existence of genes encoding for proteins directly involved in the transport of Mg2+ through the cytoplasmic membrane have accumulated over the last few years. Gene ACDP2 (ancient conserved domain protein 2; old name CNNM2, cyclin M2) is one such gene. ACDP2 is a distant homologue of the bacterial gene corC, which is known to be involved in cobalt resistance. We have previously demonstrated that the over-expression of the human Mg2+ carrier SLC41A1 partly complements the Mg2+-dependent growth deficiency of Salmonella strain MM281 (triple disruptant in genes: mgtA, mgtB and corA) cultivated in media containing growth non-permissive [Mg2+]e. We have used the same approach to examine whether over-expressed human ACDP2 has a similar efficacy to complement growth deficiency of the MM281 strain in media containing growth non-permissive [Mg2+]e. Two splicing variants of the ACDP2 gene have been tested. Here, we show that over-expressed isomorph 1 is efficient in restoring growth of the MM281 strain in media containing growth non-permissive [Mg2+]e, whereas isomorph 2 is not. Therefore, we conclude that ACDP2sp.v.1 is a functional Mg2+-transporting entity per se. Our conclusion is supported by the measurable Mg2+ influx seen in MM281 bacteria over-expressing ACDP2sp.v.1 but not in MM281 bacteria over-expressing ACDP2sp.v.2 or in cells transformed with the empty vector.


Clinical Science | 2015

PARK7/DJ-1 dysregulation by oxidative stress leads to magnesium deficiency: implications in degenerative and chronic diseases

Martin Kolisek; Augusto C. Montezano; Gerhard Sponder; Aikaterini Anagnostopoulou; Juergen Vormann; Rhian M. Touyz; Jörg R. Aschenbach

Disturbed magnesium (Mg(2+)) homoeostasis and increased levels of OS (oxidative stress) are associated with poor clinical outcomes in patients suffering from neurodegenerative, cardiovascular and metabolic diseases. Data from clinical and animal studies suggest that MD (Mg(2+) deficiency) is correlated with increased production of ROS (reactive oxygen species) in cells, but a straightforward causal relationship (including molecular mechanisms) between the two conditions is lacking. The multifactorial protein PARK7/DJ-1 is a major antioxidant protein, playing a key role in cellular redox homoeostasis, and is a positive regulator of AR (androgen receptor)-dependent transcription. SLC41A1 (solute carrier family 41 member 1), the gene encoding a ubiquitous cellular Mg(2+)E (Mg(2+)efflux) system, has been shown to be regulated by activated AR. We hypothesize that overexpression/up-regulation of PARK7/DJ-1, attributable to OS and related activation of AR, is an important event regulating the expression of SLC41A1 and consequently, modulating the Mg(2+)E capacity. This would involve changes in the transcriptional activity of PARK7/DJ-1, AR and SLC41A1, which may serve as biomarkers of intracellular MD and may have clinical relevance. Imipramine, in use as an antidepressant, has been shown to reduce the Mg(2+)E activity of SLC41A1 and OS. We therefore hypothesize further that administration of imipramine or related drugs will be beneficial in MD- and OS-associated diseases, especially when combined with Mg(2+) supplementation. If proved true, the OS-responsive functional axis, PARK7/DJ-1-AR-SLC41A1, may be a putative mechanism underlying intracellular MD secondary to OS caused by pro-oxidative stimuli, including extracellular MD. Furthermore, it will advance our understanding of the link between OS and MD.


Pflügers Archiv: European Journal of Physiology | 2016

Human CNNM2 is not a Mg 2+ transporter per se

Gerhard Sponder; Lucia Mastrototaro; Katharina Kurth; Lucia Merolle; Zheng Zhang; Nasrin Abdulhanan; Alina Smorodchenko; Katharina Wolf; Andrea Fleig; Reinhold Penner; Stefano Iotti; Jörg R. Aschenbach; Jürgen Vormann; Martin Kolisek

CNNM2 is associated with the regulation of serum Mg concentration, and when mutated, with severe familial hypomagnesemia. The function and cellular localization of CNNM2 and its isomorphs (Iso) remain controversial. The objective of this work was to examine the following: (1) the transcription-responsiveness of CNNM2 to Mg starvation, (2) the cellular localization of Iso1 and Iso2, (3) the ability of Iso1 and Iso2 to transport Mg2+, and (4) the complex-forming ability and spectra of potential interactors of Iso1 and Iso2. The five main findings are as follows. (1) Mg-starvation induces CNNM2 overexpression that is markedly higher in JVM-13 cells (lymphoblasts) compared with Jurkat cells (T-lymphocytes). (2) Iso1 and Iso2 localize throughout various subcellular compartments in transgenic HEK293 cells overexpressing Iso1 or Iso2. (3) Iso1 and Iso2 do not transport Mg2+ in an electrogenic or electroneutral mode in transgenic HEK293 cells overexpressing Iso1 or Iso2. (4) Both Iso1 and Iso2 form complexes of a higher molecular order. (5) The spectrum of potential interactors of Iso1 is ten times smaller than that of Iso2. We conclude that sensitivity of CNNM2 expression to extracellular Mg2+ depletion depends on cell type. Iso1 and Iso2 exhibit a dispersed pattern of cellular distribution; thus, they are not exclusively integral to the cytoplasmic membrane. Iso1 and Iso2 are not Mg2+ transporters per se. Both isomorphs form protein complexes, and divergent spectra of potential interactors of Iso1 and Iso2 indicate that each isomorph has a distinctive function. CNNM2 is therefore the first ever identified Mg2+ homeostatic factor without being a Mg2+ transporter per se.


Hypertension in Pregnancy | 2013

SLC41A1 is the only magnesium responsive gene significantly overexpressed in placentas of preeclamptic women

Martin Kolisek; Gerhard Sponder; Saba Javaid; Katharina Kurth; Axel Nestler; Stefan Verlohren; Fernando Guerrero-Romero; Jürgen Vormann

Objective: To examine expression profile of magnesium responsive genes (MRGs) in placentas of normoevolutive and preeclamptic women. Methods: The expression profiles of MRGs were determined in placentas of normoevolutive (N = 26) and preeclamptic (N = 25) women by RT-qPCR. Results: Among all tested MRGs (9) only SLC41A1 (encoding for Na+/Mg2+ exchanger) was significantly overexpressed in ∼54.2% of preeclamptic (n = 24) and in ∼9.5% of normoevolutive (n = 21) specimens. On average, SLC41A1 was overexpressed sixfold in the preeclamptic group. Presence of SLC41A1 in placentas was confirmed by Western blot analysis. Conclusion. SLC41A1 is significantly overexpressed in nearly 55% of preeclamptic placentas. This may indicate a direct contribution of changed Mg homeostasis in the development of preeclampsia.


Wiley Interdisciplinary Reviews: Membrane Transport and Signaling | 2013

Solute carrier family SLC41: what do we really know about it?

Andrea Fleig; Monika Schweigel-Röntgen; Martin Kolisek

The 41st family of solute carriers (SLC41) comprises three members A1, A2 and A3, which are distantly homologous to bacterial Mg2+ channel MgtE. SLC41A1 was recently characterized as being an Na+/Mg2+ exchanger (NME; a predominant cellular Mg2+ efflux system). Little is known about the exact function of SLC41A2 and SLC41A3, although, these proteins have also been linked to Mg2+ transport in human (animal) cells. The molecular biology (including membrane topology, cellular localization, transcriptomics and proteomics) of SLC41A2 and SLC41A3 compared with SLC41A1 has only been poorly explored. Significantly more data with regard to function, functional regulation, involvement in cellular signalling, complex-forming ability, spectrum of binding partners and involvement in the pathophysiology of human diseases are available for SLC41A1. Three recent observations namely the identification of the null mutation, c.698G>T, in SLC41A1 underlying the nephronophthisis-like phenotype, the recognition of a putative link between SLC41A1 and Parkinsons disease, and the observation that nearly 55% of preeclamptic placental samples overexpress SLC41A1, marks the protein as a possible therapeutic target of these diseases. A potential role of the SLC41 family of Mg2+ transporters in the pathophysiology of human diseases is further substantiated by the finding that SLC41A3 knockout mice develop abnormal locomotor coordination.


Journal of Nutrition | 2015

Insulin Modulates the Na+/Mg2+ Exchanger SLC41A1 and Influences Mg2+ Efflux from Intracellular Stores in Transgenic HEK293 Cells

Lucia Mastrototaro; Uwe Tietjen; Gerhard Sponder; Jürgen Vormann; Jörg R. Aschenbach; Martin Kolisek

BACKGROUND Magnesium deficiency is a common complication of diabetes with an unclear molecular background. OBJECTIVE We investigated the effect of the insulin (INS)-signaling pathway (ISP) on the regulation of Mg(2+) efflux (Mg(2+)E) conducted by solute carrier family 41, member A1 (SLC41A1; activated by protein kinase A) in transgenic human embryonic kidney (HEK) 293 cells. METHODS HEK293 cells overexpressing SLC41A1 were loaded with the Mg(2+) fluorescent indicator mag-fura-2 and Mg(2+). Measurements of Mg(2+)E were conducted in Mg(2+)-free buffer by using fast-filter fluorescence spectrometry. We examined the effects of INS, inhibitors of ISP or p38 mitogen-activated protein kinase (p38 MAPK), an activator of adenylate cyclase (ADC), and their combinations on SLC41A1-attributed Mg(2+)E. RESULTS The application of 400 μU/mL INS inhibited SLC41A1-mediated Mg(2+)E by up to 50.6% compared with INS-untreated cells (P < 0.001). Moreover, INS evoked the early onset of Mg(2+) release from intracellular stores. The application of 0.1 μM wortmannin or 10 μM zardaverine (both ISP inhibitors) restored SLC41A1 Mg(2+)E capacity in the presence of INS to the same levels in INS-untreated cells. The simultaneous application of 10 μM forskolin, an ADC activator, and INS resulted in a reduction of Mg(2+)E of up to 59% compared with untreated cells (P < 0.001), which was comparable to that in cells treated with INS alone. Inhibition of p38 MAPK with 10 μM SB 202190 (SB) in the absence of INS resulted in a decrease (P < 0.001) of SLC41A1-dependent Mg(2+)E (by up to 49%) compared with Mg(2+)E measured in untreated cells. Simultaneous exposure of cells to SB and INS had a stronger inhibitory effect on SLC41A1 activity than INS alone (P < 0.05). CONCLUSIONS INS affects intracellular Mg(2+) concentration in transgenic HEK293 cells by regulating SLC41A1 activity (via ISP) and by influencing the compartmentalization and cellular distribution of Mg(2+). In addition, p38 MAPK activates SLC41A1 independently of INS action.

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Gerhard Sponder

Free University of Berlin

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Jürgen Vormann

Free University of Berlin

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Andrea Fleig

The Queen's Medical Center

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Andreas Beck

University of Hawaii at Manoa

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Reinhold Penner

The Queen's Medical Center

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