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001-es BibID:BIBFORM062460
035-os BibID:(Cikkazonosító)18397 (WOS)000367035500001 (Scopus)84951782397
Első szerző:Bartók Ádám (biotechnológus)
Cím:An engineered scorpion toxin analogue with improved Kv1.3 selectivity displays reduced conformational flexibility / Adam Bartok, Krisztina Fehér, Andrea Bodor, Kinga Rákosi, Gábor K. Tóth, Katalin E. Kövér, Gyorgy Panyi, Zoltan Varga
Dátum:2015
ISSN:2045-2322
Megjegyzések:The voltage-gated Kv1.3 K(+) channel plays a key role in the activation of T lymphocytes. Kv1.3 blockers selectively suppress immune responses mediated by effector memory T cells, which indicates the great potential of selective Kv1.3 inhibitors in the therapy of certain autoimmune diseases. Anuroctoxin (AnTx), a 35-amino-acid scorpion toxin is a high affinity blocker of Kv1.3, but also blocks Kv1.2 with similar potency. We designed and produced three AnTx variants: ([F32T]-AnTx, [N17A]-AnTx, [N17A/F32T]-AnTx) using solid-phase synthesis with the goal of improving the selectivity of the toxin for Kv1.3 over Kv1.2 while keeping the high affinity for Kv1.3. We used the patch-clamp technique to determine the blocking potency of the synthetic toxins on hKv1.3, mKv1.1, hKv1.2 and hKCa3.1 channels. Of the three variants [N17A/F32T]-AnTx maintained the high affinity of the natural peptide for Kv1.3 but became more than 16000-fold selective over Kv1.2. NMR data and molecular dynamics simulations suggest that the more rigid structure with restricted conformational space of the double substituted toxin compared to the flexible wild-type one is an important determinant of toxin selectivity. Our results provide the foundation for the possibility of the production and future therapeutic application of additional, even more selective toxins targeting various ion channels.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
T lymphocytes
scorpion toxin
patch-clamp technique
Megjelenés:Scientific Reports. - 5 : 18397 (2015), p. 1-13. -
További szerzők:Fehér Krisztina (1974-) (vegyész) Bodor Andrea Rákosi Kinga Tóth Gábor K. Kövér Katalin, E. (1956-2023) (vegyész) Panyi György (1966-) (biofizikus) Varga Zoltán (1969-) (biofizikus, szakfordító)
Pályázati támogatás:TÁMOP-4.2.2/A-11/1/KONV-2012-0025
TÁMOP
TÁMOP-4.2.2/A-11/1/ KONV-2012-0035
TÁMOP
TÁMOP-4.2.1./B-09/KMR-2010-0003
TÁMOP
K 75904
OTKA
NK 101337
OTKA
K 105459
OTKA
4.2.4.A/2-11/1-2012-0001
TÁMOP
KTIA_ NAP_13-2-2015-0009
Egyéb
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Intézményi repozitóriumban (DEA) tárolt változat
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2.

001-es BibID:BIBFORM060448
Első szerző:Bartók Ádám (biotechnológus)
Cím:Potassium Channel-Blocking Peptide Toxins from Scorpion Venom / Adam Bartok, Gyorgy Panyi, Zoltan Varga
Dátum:2015
Megjegyzések:n the last three decades, numerous peptides isolated from scorpion venom have been identified as members of the KTx, or potassium channel-blocking group of toxins. This chapter provides an overview of the four families of KTx, named ?, ?, ?, and ?, discussing characteristic structural features and K+ channel selectivity of these peptides. Methods of KTx peptide identification and isolation, as well as techniques for the assessment of the efficacy of potassium channel blockade, are described. With the advancement of molecular biology, molecular dynamics simulations, and nuclear magnetic resonance (NMR) techniques, many details of the toxin-channel interaction have been clarified and models of different modes of toxin binding have emerged. A table summarizing all currently known 133 members of the KTx group of peptides is presented, including their systematic and common names, along with their affinities for the major target K+ channels, which may be in the low picomolar range. These peptides have provided vital information about the topology of the external pore region of K+ channels highlighting similarities and even minute differences. In addition to being valuable exploratory molecular tools, peptide blockers of K+ channels with high affinity and selectivity offer great potential for therapeutic use in a wide variety of diseases as was illustrated by several successful trials in animal models.
ISBN:978 94 007 6647 1
Tárgyszavak:Orvostudományok Elméleti orvostudományok könyvfejezet
Potassium Channel
Peptide Toxins
Megjelenés:Toxinology : Scorpion Venoms / eds. Gopalakrishnakone, P., Possani, L.D., F. Schwartz, E., Rodríguez de la Vega. - p. 493-527. -
További szerzők:Panyi György (1966-) (biofizikus) Varga Zoltán (1969-) (biofizikus, szakfordító)
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Intézményi repozitóriumban (DEA) tárolt változat
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3.

001-es BibID:BIBFORM052924
Első szerző:Bartók Ádám (biotechnológus)
Cím:Margatoxin is a non-selective inhibitor of human Kv1.3 K+ channels / Adam Bartok, Agnes Toth, Sandor Somodi, Tibor G. Szanto, Peter Hajdu, Gyorgy Panyi, Zoltan Varga
Dátum:2014
ISSN:0041-0101
Megjegyzések:Margatoxin (MgTx), an alpha-KTx scorpion toxin, is considered a selective inhibitor of the Kv1.3 K+ channel. This peptide is widely used in ion channel research; however, a comprehensive study of its selectivity with electrophysiological methods has not been published yet. The lack of selectivity might lead to undesired side effects upon therapeutic application or may lead to incorrect conclusion regarding the role of a particular ion channel in a physiological or pathophysiological response either in vitro or in vivo. Using the patch-clamp technique we characterized the selectivity profile of MgTx using L929 cells expressing mKv1.1 channels, human peripheral lymphocytes expressing Kv1.3 channels and transiently transfected tsA201 cells expressing hKv1.1, hKv1.2, hKv1.3, hKv1.4-IR, hKv1.5, hKv1.6, hKv1.7, rKv2.1, Shaker-IR, hERG, hKCa1.1, hKCa3.1 and hNav1.5 channels. MgTx is indeed a high affinity inhibitor of Kv1.3 (Kd = 11.7 pM) but is not selective, it inhibits the Kv1.2 channel with similar affinity (Kd = 6.4 pM) and Kv1.1 in the nanomolar range (Kd = 4.2 nM). Based on our comprehensive data MgTX has to be considered a non-selective Kv1.3 inhibitor, and thus, experiments aiming at elucidating the significance of Kv1.3 in in vitro or in vivo physiological responses have to be carefully evaluated.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
ion channel
potassium channel
scorpion toxin
margatoxin
Megjelenés:Toxicon. - 87 (2014), p. 6-16. -
További szerzők:Tóth Ágnes (1983-) (biofizikus) Somodi Sándor (1977-) (belgyógyász) Szántó Gábor Tibor (1980-) (vegyész) Hajdu Péter (1975-) (biofizikus) Panyi György (1966-) (biofizikus) Varga Zoltán (1969-) (biofizikus, szakfordító)
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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4.

001-es BibID:BIBFORM062511
Első szerző:Fehér Krisztina (vegyész)
Cím:Probing pattern and dynamics of disulfide bridges using synthesis and NMR of an ion channel blocker peptide toxin with multiple diselenide bonds / Krisztina Fehér, István Timári, Kinga Rákosi, János Szolomájer, Tünde Z. Illyés, Ádám Bartók, Zoltán Varga, György Panyi, Gábor K. Tóth, Katalin E. Kövér
Dátum:2016
ISSN:2041-6520 2041-6539
Megjegyzések:Anuroctoxin (AnTx), a 35-amino-acid scorpion toxin containing four disulfide bridges, is a high affinity blocker of the voltage-gated potassium channel Kv1.3, but also blocks Kv1.2. To improve potential therapeutic use of the toxin, we have designed a double substituted analog, [N17A/F32T]-AnTx, which showed comparable Kv1.3 affinity to the wild-type peptide, but also a 2500-fold increase in the selectivity for Kv1.3 over Kv1.2. In the present study we have achieved the chemical synthesis of a Sec-analog in which all cysteine (Cys) residues have been replaced by selenocysteine (Sec) forming four diselenide bonds. To the best of our knowledge this is the first time to replace, by chemical synthesis, all disulfide bonds with isosteric diselenides in a peptide/protein. Gratifyingly, the key pharmacological properties of the Sec-[N17A/F32T]-AnTx are retained since the peptide is functionally active. We also propose here a combined experimental and theoretical approach including NOE- and 77Se-based NMR supplemented by MD simulations for conformational and dynamic characterization of the Sec-[N17A/F32T]-AnTx. Using this combined approach allowed us to attain unequivocal assignment of all four diselenide bonds and supplemental MD simulations allowed characterization of the conformational dynamics around each disulfide/diselenide bridge.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
peptide toxin
ion channels
disulfide bridge
Megjelenés:Chemical Science 7 (2016), p. 2666-2673. -
További szerzők:Timári István (1989-) (vegyész) Rákosi Kinga Szolomájer János Illyés Tünde Zita (1970-) (kémia-fizika szakos tanár) Bartók Ádám (1984-) (biotechnológus) Varga Zoltán (1969-) (biofizikus, szakfordító) Panyi György (1966-) (biofizikus) Tóth Gábor K. Kövér Katalin, E. (1956-2023) (vegyész)
Pályázati támogatás:TAMOP-4.2.2/A-11/1/KONV-2012-0025
TÁMOP
TAMOP-4.2.2/A-11/1/KONV-2012-0035
TÁMOP
OTKA K 75904
OTKA
OTKA NK 101337
OTKA
OTKA K 105459
OTKA
KTIA_NAP_13-2-2015?0009
Egyéb
KTIA_13_NAP-A-III/8
Egyéb
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Intézményi repozitóriumban (DEA) tárolt változat
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5.

001-es BibID:BIBFORM082763
035-os BibID:(cikkazonosító)166 (WOS)000513236100002 (Scopus)85076716316
Első szerző:Matta Csaba (molekuláris biológus, genetikus, angol szakfordító)
Cím:N-methyl-D-aspartate (NMDA) receptor expression and function is required for early chondrogenesis / Csaba Matta, Tamás Juhász, János Fodor, Tibor Hajdú, Éva Katona, Csilla Szűcs-Somogyi, Roland Takács, Judit Vágó, Tamás Oláh, Ádám Bartók, Zoltan Varga, Gyorgy Panyi, László Csernoch, Róza Zákány
Dátum:2019
ISSN:1478-811X
Megjegyzések:Background In vitro chondrogenesis depends on the concerted action of numerous signalling pathways, many of which are sensitive to the changes of intracellular Ca2+ concentration. N-methyl-D-aspartate (NMDA) glutamate receptor is a cation channel with high permeability for Ca2+. Whilst there is now accumulating evidence for the expression and function of NMDA receptors in non-neural tissues including mature cartilage and bone, the contribution of glutamate signalling to the regulation of chondrogenesis is yet to be elucidated. Methods We studied the role of glutamatergic signalling during the course of in vitro chondrogenesis in high density chondrifying cell cultures using single cell fluorescent calcium imaging, patch clamp, transient gene silencing, and western blotting. Results Here we show that key components of the glutamatergic signalling pathways are functional during in vitro chondrogenesis in a primary chicken chondrogenic model system. We also present the full glutamate receptor subunit mRNA and protein expression profile of these cultures. This is the first study to report that NMDA-mediated signalling may act as a key factor in embryonic limb bud-derived chondrogenic cultures as it evokes intracellular Ca2+ transients, which are abolished by the GluN2B subunit-specific inhibitor ifenprodil. The function of NMDARs is essential for chondrogenesis as their functional knock-down using either ifenprodil or GRIN1 siRNA temporarily blocks the differentiation of chondroprogenitor cells. Cartilage formation was fully restored with the re-expression of the GluN1 protein. Conclusions We propose a key role for NMDARs during the transition of chondroprogenitor cells to cartilage matrix-producing chondroblasts.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Chondrocyte
Chondrogenesis
Glutamate signalling
Glycine
N-methyl-D-aspartate receptor
NMDAR
Single cell calcium imaging
siRNA
Megjelenés:Cell Communication and Signaling. - 17 : 1 (2019), p. 166. -
További szerzők:Juhász Tamás (1976-) (biológus, orvosbiológus) Fodor János (1973-) (élettanász, biotechnológus) Hajdú Tibor (1988-) (általános orvos) Katona Éva (1986-) (molekuláris biológus) Somogyi Csilla (1983-) (biológus, angol-magyar szakfordító) Takács Roland Ádám (1985-) (molekuláris biológus, biokémikus) Vágó Judit (1990-) (molekuláris biológus) Oláh Tamás (1983-) (élettanász) Bartók Ádám (1984-) (biotechnológus) Varga Zoltán (1969-) (biofizikus, szakfordító) Panyi György (1966-) (biofizikus) Csernoch László (1961-) (élettanász) Zákány Róza (1963-) (anatómus-, kötőszövetbiológus)
Pályázati támogatás:EFOP-3.6.2-16-2017-00006
EFOP
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Intézményi repozitóriumban (DEA) tárolt változat
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6.

001-es BibID:BIBFORM062512
Első szerző:Pethő Zoltán (orvos)
Cím:The anti-proliferative effect of cation channel blockers in T lymphocytes depends on the strength of mitogenic stimulation / Zoltan Petho, Andras Balajthy, Adam Bartok, Krisztian Bene, Sandor Somodi, Orsolya Szilagyi, Eva Rajnavolgyi, Gyorgy Panyi, Zoltan Varga
Dátum:2016
ISSN:0165-2478
Megjegyzések:Ion channels are crucially important for the activation and proliferation of T lymphocytes, and thus, for the function of the immune system. Previous studies on the effects of channel blockers on T cell proliferation reported variable effectiveness due to differing experimental systems. Therefore our aim was to investigate how the strength of the mitogenic stimulation influences the efficiency of cation channel blockers in inhibiting activation, cytokine secretion and proliferation of T cells under standardized conditions. Human peripheral blood lymphocytes were activated via monoclonal antibodies targeting the TCR-CD3 complex and the co-stimulator CD28. We applied the blockers of Kv1.3 (Anuroctoxin), KCa3.1 (TRAM-34) and CRAC (2-Apb) channels of T cells either alone or in combination with rapamycin, the inhibitor of the mammalian target of rapamycin (mTOR). Five days after the stimulation ELISA and flow cytometric measurements were performed to determine IL-10 and IFN-? secretion, cellular viability and proliferation. Our results showed that ion channel blockers and rapamycin inhibit IL-10 and IFN-? secretion and cell division in a dose-dependent manner. Simultaneous application of the blockers for each channel along with rapamycin was the most effective, indicating synergy among the various activation pathways. Upon increasing the extent of mitogenic stimulation the anti-proliferative effect of the ion channel blockers diminished. This phenomenon may be important in understanding the fine-tuning of T cell activation.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Immune regulation
Rapamycin
ion channel
Cytokine secretion
T cells
Megjelenés:Immunology Letters 171 (2016), p. 60-69. -
További szerzők:Balajthy András (1988-) (általános orvos) Bartók Ádám (1984-) (biotechnológus) Bene Krisztián (1986-) (Biológus) Somodi Sándor (1977-) (belgyógyász) Szilágyi Orsolya (1985-) (molekuláris biológus, biokémikus) Rajnavölgyi Éva (1950-) (immunológus) Panyi György (1966-) (biofizikus) Varga Zoltán (1969-) (biofizikus, szakfordító)
Pályázati támogatás:KTIA NAP 13-2-2015-0009
Egyéb
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Intézményi repozitóriumban (DEA) tárolt változat
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7.

001-es BibID:BIBFORM028213
Első szerző:Varga Zoltán (biofizikus, szakfordító)
Cím:Switch of voltage-gated k channel expression in the plasma membrane of chondrogenic cells affects cytosolic ca-oscillations and cartilage formation / Varga Zoltán, Juhász Tamás, Matta Csaba, Fodor János, Katona Eva, Bartok Adam, Oláh Tamás, Sebe Attila, Csernoch László, Panyi György, Zákány Róza
Dátum:2011
Megjegyzések:Understanding the key elements of signaling of chondroprogenitor cells at the earliest steps of differentiation may substantially improve our opportunities for the application of mesenchymal stem cells in cartilage tissue engineering, which is a promising approach of regenerative therapy of joint diseases. Ion channels, membrane potential and Ca(2+)-signaling are important regulators of cell proliferation and differentiation. Our aim was to identify such plasma membrane ion channels involved in signaling during chondrogenesis, which may serve as specific molecular targets for influencing chondrogenic differentiation and ultimately cartilage formation. METHODOLOGY/PRINCIPAL FINDINGS:Using patch-clamp, RT-PCR and Western-blot experiments, we found that chondrogenic cells in primary micromass cell cultures obtained from embryonic chicken limb buds expressed voltage-gated Na(V)1.4, K(V)1.1, K(V)1.3 and K(V)4.1 channels, although K(V)1.3 was not detectable in the plasma membrane. Tetrodotoxin (TTX), the inhibitor of Na(V)1.4 channels, had no effect on cartilage formation. In contrast, presence of 20 mM of the K(+) channel blocker tetraethyl-ammonium (TEA) during the time-window of the final commitment of chondrogenic cells reduced K(V) currents (to 27?3% of control), cell proliferation (thymidine incorporation: to 39?4.4% of control), expression of cartilage-specific genes and consequently, cartilage formation (metachromasia: to 18.0?6.4% of control) and also depolarized the membrane potential (by 9.3?2.1 mV). High-frequency Ca(2+)-oscillations were also suppressed by 10 mM TEA (confocal microscopy: frequency to 8.5?2.6% of the control). Peak expression of TEA-sensitive K(V)1.1 in the plasma membrane overlapped with this period. Application of TEA to differentiated chondrocytes, mainly expressing the TEA-insensitive K(V)4.1 did not affect cartilage formation.CONCLUSIONS/SIGNIFICANCE:These data demonstrate that the differentiation and proliferation of chondrogenic cells depend on rapid Ca(2+)-oscillations, which are modulated by K(V)-driven membrane potential changes. K(V)1.1 function seems especially critical during the final commitment period. We show the critical role of voltage-gated cation channels in the differentiation of non-excitable cells with potential therapeutic use.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:PLoS One. - 6 : 11 (2011), p. e27957. -
További szerzők:Juhász Tamás (1976-) (biológus, orvosbiológus) Matta Csaba (1980-) (molekuláris biológus, genetikus, angol szakfordító) Fodor János (1973-) (élettanász, biotechnológus) Katona Éva (1986-) (molekuláris biológus) Bartók Ádám (1984-) (biotechnológus) Oláh Tamás (1983-) (élettanász) Sebe Attila Csernoch László (1961-) (élettanász) Panyi György (1966-) (biofizikus) Zákány Róza (1963-) (anatómus-, kötőszövetbiológus)
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Intézményi repozitóriumban (DEA) tárolt változat
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