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1

Elektrofizjologiczny opis transmisji synaptycznej i jej modulacji przez czynniki farmakologiczne

100%
Mozrzymas J. W.
Postępy Higieny i Medycyny Doświadczalnej
|
2000
|
tom 54
|
nr 3
403-416
2

Electrophysiological description of mechanisms determining synaptic transmission and its modulation

100%
Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2008
|
tom 68
|
nr 2
Signal integration in neurons is a complex process that depends on e.g. the kinetics of synaptic currents, distribution of synaptic connections as well as passive and excitatory membrane properties. The time course of synaptic currents is largely determined by the kinetics of the postsynaptic receptors and the time course of synaptic neurotransmitter concentration. The analysis of current responses to rapid agonist applications provides the means to study the ligand-gated receptor gating but experimentally based estimation of neurotransmitter transient at central synapses was an important challenge during the last decade. Both theoretical as well as experimentally based approaches indicated that synaptic agonist transient is very brief, implying that the activation of postsynaptic receptors occurs in conditions of extreme non-equilibrium. Such a dynamic pattern of activation of postsynaptic receptors has a crucial impact not only on the kinetics of synaptic currents but also on their susceptibility to pharmacological modulation.
3

Sygnaly elektryczne jako uniwersalny mechanizm szybkiego przekazywania informacji miedzy komorkami. Mechanizmy modulacji w warunkach fizjologicznych i patologicznych

100%
Mozrzymas J. W.
Postępy Higieny i Medycyny Doświadczalnej
|
1999
|
tom 53
|
nr 2
247-261
4

Mechanisms determining the shape and pharmacological modulation of gazaergic synaptic currents

100%
Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2001
|
tom 61
|
nr 3
5

Modulation of GABAergie currents:a ciose look at the time scale of synaptic transmission

100%
Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2005
|
tom 65
|
nr 3
6

Electrophysiological studies on the mechanisms determining the kinetics and pharmacological modulation of GABAergic synaptic transmission

100%
Mozrzymas J. W.
Cellular and Molecular Biology Letters
|
2002
|
tom 07
|
nr Suppl.
7

Chlorpromazine effects on NMDA and non-NMDA glutamate receptors in cultured rat hippocampal neurons

63%
Zarnowska E. D., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2001
|
tom 61
|
nr 3
8

Matrix metalloproteinase activity regulates LTP through L-type voltage-gated calcium channel modulation

63%
Wiera G., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2014
|
tom 74
|
nr 3
Long-term synaptic plasticity at hippocampal CA3-CA1 synapses exhibit NMDAR- and L-type calcium channel (VDCC)- dependent components. To address the role of MMP proteases in mechanism of LTP induction, we used field potentials recordings in acute mice brain slices. LTP was induced by 200 Hz tetanus. We have found that MMP inhibitor (NNGH, inhibits mainly MMP-3) disrupts 200 Hz-LTP (CTR: 164±11%, n=9; NNGH: 117±7%, n=7, P<0.01). Next, we dissected two components of 200 Hz-LTP using nifedipine (L-type blocker) and APV (NMDAR inhibitor). MMP blockade with NNGH prevented only vdccLTP (nmdaLTP in the presence of nifedipine: 140±6%, n=8; nifedipine+NNGH: 141±8%, n=6 P=0.93; vdccLTP in the presence of APV: 168±27%, n=7; APV+NNGH: 110±13%, n=6, P<0.05). Our observations show that MMP activity (presumably MMP3) specifically regulates VDCC-dependent component of hippocampal LTP. Supported by NCN grants: NN401541540 and ETIUDA 2013/08/T/ NZ3/00999.
9

Molecular mechanisms of proton modulation in the GABAA receptor as compared to low pH activation scheme in the GLIC ion

63%
Michalowski M. A., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
|
nr Suppl.1
INTRODUCTION: The GABAA receptor (GABAAR) belongs to a family of pentameric ligand gated ion channels (pLGICs). Another member of this family, bacterial GLIC, is directly activated by protons. Recent studies showed that protonation of GLIC’s E35 residue starts a cascade of interactions that end at the channel pore and lead to its opening. GABAAR preserves sensitivity to protons, and ligand elicited currents can be modulated by them. The exact molecular mechanism of this action is not known. AIM(S): This study aims to elucidate the molecular action and sensitivity of GABAAR to protons, and to answer the question of whether those mechanism are similar to proton activation in GLIC. METHOD(S): Sequences of pLGICs were obtained from the UniProt database and aligned using T‑Coffe. Additional manual refinements and alignment analysis was done in JalView. Structures of GLIC and GABAAR were obtained from RCSB PDB. Homology modeling was done using Modeller. pKa values of GABAAR residues were assessed with PropKa 3. Structure analysis and visualization was done in VMD. RESULTS: Using in silico methods, pKa values of GABAAR residues were assessed, and we determined the positions that are homologous to proton sensitive residues of GLIC. In GABAAR, no proton sensitive residues at positions homologous to GLIC E35 were detected. Instead, residues with pKa values in proximity of physiological values was found at the cys‑loop (e.g. E138 and H142 at α subunit and E150 and H156 at γ subunit), GABA binding site (βE155), upper part of ion pore (βH267 and βE270), and in its bottom part (intracellular part of the receptor, αE303 and βE313). CONCLUSIONS: The molecular scheme of low pH activation of GLIC is not preserved in GABAAR. Lack of proton sensitive residue at positions homologous to E35, and the presence of multiple possibly proton susceptible residues spread within receptor structure indicate a complex and scattered mechanism of modulation. FINANCIAL SUPPORT: Supported by National Science Center grant 2018/29/N/NZ1/02834.
10

Erythropoietin affects GABAergic transmission in hippocampal neurons in vitro

63%
Wojtowicz T., Mozrzymas J. W.
Cellular and Molecular Biology Letters
|
2008
|
tom 13
|
nr 4
649-655
Erythropoietin is a potent regulator of erythropoiesis. It acts via the specific membrane receptor (EpoR). Erythropoietin is also known to be present in the central nervous system, and its concentration and the expression of EpoR change during development, which raises the possibility that this modulator might be involved in the regulation of neuronal functions in the developing brain. The GABAergic system undergoes profound changes during development and is particularly susceptible to modulation by endogenous factors. Therefore, we decided to investigate the impact of Epo on GABAergic transmission in hippocampal neurons developing in vitro. An analysis of miniature IPSCs (mIPSCs) revealed that a long-term treatment with Epo (48 or 72 h) resulted in a major acceleration of the decaying phase of these currents while the amplitude and current frequency remained unchanged. Interestingly, this effect was restricted to the youngest considered age group (6-8 DIV), indicating that Epomediated modulation of mIPSCs depends on the developmental stage of the neurons. We conclude that Epo may exert a modulatory action on GABAergic transmission in developing neural networks.
11

Extracellular zink inhibits the activity of Kv1.3 channels in human T lymphocytes

63%
Teisseyre A., Mozrzymas J. W.
Cellular and Molecular Biology Letters
|
2001
|
tom 06
|
nr 2A
425
12

The role of matrix metalloprotease subtypes in EPSP-to-spike (E-S) plasticity in CA3 associational network

63%
Wojtowicz T. W., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
Learning and memory formation are often linked to long-term synaptic plasticity but some components of memory storage are coded by nonsynaptic changes, i.e. neuronal excitability. Matrix metalloproteases (MMPs) play a crucial role in long-term synaptic plasticity, but to what extent they affect other neuronal functions remains poorly understood. Here we studied the impact of MMP-3 and MMP-2/9 specific inhibitors on evoked EPSPs and population spikes (PS) in CA3 hippocampal autoassociative network in rat P30–P60 brain slices. We found that MMPs inhibition reduced long-term E-S coupling and spiking coherence evoked with stimulation of associational/commisural synapses alone (4×100 Hz) or paired in bursts with mossy-fibers. Moreover, broad spectrum MMPs inhibitor did not occlude with E-S plasticity recorded in the presence of GABAARs or L-type calcium channels blockers but significantly reduced LTP of NMDAR-mediated EPSPs. Finally, MMPs inhibition determined the saturation level of E-S coupling depending on synaptic activity pattern. In conclusion, our data provide a novel link between MMPs activity (particularly MMP-3), postsynaptic depolarization and neural excitability. By regulating E-S plasticity and by limiting the number of neurons firing, MMPs could influence information processing in CA3 associational network. Supported by MNiSW grant “Iuventus Plus” IP2010_047870 and partially by 3/Pbmn and N N401541540 grant.
13

MMP-3 and MMP-9 divergently regulate LTP in hippocampal mosy fiber-CA3 and CA3-CA1 projections

63%
Wiera G., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
Matrix metalloproteinases (MMPs) comprise a family of proteolytic enzymes that modify membrane and extracellular matrix proteins. Broad-spectrum MMP inhibitors were shown to impair LTP consolidation in two hippocampal projections: mossy fiber (MF)-CA3 and CA3-CA1 which deeply differ in LTP induction as well as in expression sites and induction mechanisms. The aim of this study was to address the specific roles of MMP-3 and gelatinases in LTP in these projections. Using field potentials recording in acute mice brain slices we have shown that specific MMP-3 inhibitor (NNGH) disrupts LTP late phase in CA3-CA1 pathway (NNGH: 119 ± 10% of baseline two hours after induction, n=9; CTR: 177 ± 29%, n=8; P=0.01) but does not affect LTP in MF-CA3 (NNGH: 186 ± 27%, n=7; CTR: 172 ± 11%; n=7, P=0.34). Another MMP-3 inhibitor UK356618 gave similar results. Interestingly, knock-out mice without functional MMP-9 show impaired long term plasticity in MF-CA3 pathway (KO: 115 ± 17%, n=8; CTR 181 ± 13%, n=13; P<0.01) and a weak if any change in LTP in CA3-CA1 projection (KO: 139 ± 8%, n=7; CTR: 159 ± 13%, n=8; P=0.22). These results suggest that the role of particular MMPs in LTP expression is not universal in considered projections. Moreover, we provide the first evidence that MMP-3 and MMP-9 proteases differentially modify LTP consolidation in the MF-CA3 and CA3-CA1 pathways. Support: NCN grant N N401541540.
14

Matrix matalloproteases regulate the extent of synaptic plasticity and spike potentiation in hippocampal CA3 association network

63%
Wojtowicz T., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2012
|
tom 72
|
nr 2
Matrix metalloproteinases (MMPs) activity support spatial and associative learning in vivo however the underlying mechanisms are poorly understood. It has been shown that MMPs inhibition impairs the maintenance of long-term potentiation (LTP) in hippocampal Sch-CA1 synapses and in mfCA3 pathways. However, it is not known whether MMPs activity influences the scaling of postsynaptic neuronal responses (population spikes, PS) typically associated with synaptic LTP. Therefore, we investigated the plasticity of evoked synaptic transmission (input) and resulting PS (output) in CA3 associative network by simultaneous double electrode extracellular field potentials recording. We found that highfrequency-induced (4 × 100 Hz) LTP of EPSPs and PS was significantly impaired in the presence of broad spectrum MMPs inhibitor FN439 while the EPSP-to-Spike (E-S) curves were right-shifted indicating that less neurons were recruited to fire for a given input. Additionally, these effects could be mimicked by application of MMP-3 inhibitor (NNGH). MMPs inhibitors did not affect input–output function of the CA3 neurons or various forms of short term-plasticity. In conclusion, MMPs and particularly MMP-3 may play an important role in the maintenance of E-S potentiation in the CA3 network and thereby may regulate formation of memory traces in this hippocampal region. Supported by IP2010_047870 grant.
15
Content available remote

The inhibitory effect of copper ions on lymphocyte Kv1.3 potassium channels

63%
Teisseyre A., Mozrzymas J. W.
Journal of Physiology and Pharmacology
|
2006
|
tom 57
|
nr 2
We applied the whole-cell patch-clamp technique to study the inhibitory effect of copper ions (Cu) on the activity of Kv1.3 channels expressed in human lymphocytes. Application of Cu reversibly inhibited the currents to about 10% of the control value in a concentration-dependent manner with the half blocking concentration of 5.28±0.5 µM and the Hill's coefficient of 3.83±0.18. The inhibitory effect was saturated at 10 µM concentration. The inhibition was time-dependent and it was correlated in time with a significant slowing of the current activation rate. In contrast the voltage dependence of activation was not changed by Cu as well as the inativation kinetics. The inhibitory effect of Cu was voltage-independent. It was also unaffected by changing the extracellular pH in the range from 6.4 to 8.4, raising the extracellular potassium concentration to 150 mM and by changing the holding potential from -90 to -60 mV. The inhibitiory effect of Cu was not changed in the presence of an equivalent concentration of Zn. Altogether, obtained data suggest that Cu inhibits Kv1.3 channels by a different mechanism than Zn and that Cu and Zn act on different binding sites. The inhibitory effect of Cu was probably due to a specific binding of Cu on binding sites on the channels. Possible physiological significance of the Cu-induced inhibition of Kv1.3 channels is discussed.
16

The influence of protons and zinc ions on the steady-state inactivation of Kv1.3 potassium channels

63%
Teisseyre A., Mozrzymas J. W.
Cellular and Molecular Biology Letters
|
2007
|
tom 12
|
nr 2
Using the whole-cell patch-clamp technique, we investigated the influence of extracellular pH and zinc ions (Zn2+) on the steady-state inactivation of Kv1.3 channels expressed in human lymphocytes. The obtained data showed that lowering the extracellular pH from 7.35 to 6.8 shifted the inactivation midpoint (Vi) by 17.4 ± 1.12 mV (n = 6) towards positive membrane potentials. This shift was statistically significant (p < 0.05). Applying 100 μM Zn2+ at pH 6.8 further shifted the Vi value by 16.55 ± 1.80 mV (n = 6) towards positive membrane potentials. This shift was also statistically significant (p < 0.05). The total shift of the Vi by protons and Zn2+ was 33.95 ± 1.90 mV (n = 6), which was significantly higher (p < 0.05) than the shift caused by Zn2+ alone. The Zn2+-induced shift of the Vi at pH 6.8 was almost identical to the shift at pH = 7.35. Thus, the proton-and Zn2+-induced shifts of the Vi value were additive. The steady-state inactivation curves as a function of membrane voltage were compared with the functions of the steady-state activation. The total shift of the steady-state inactivation was almost identical to the total shift of the steady-state activation (32.01 ± 2.10 mV, n = 10). As a result, the “windows” of membrane potentials in which the channels can be active under physiological conditions were also markedly shifted towards positive membrane potentials. The values of membrane voltage and the normalised chord conductance corresponding to the points of intersection of the curves of steady-state activation and inactivation were also calculated. The possible physiological significance of the observed modulatory effects is discussed herein.
17

Changes of GABAA receptor activation kinetics in hippocampal neurons cultured for different periods of time

63%
Mozrzymas J. W., Barberis A.
Cellular and Molecular Biology Letters
|
2004
|
tom 09
|
nr 1
Cell culture is a convenient model for pharmacokinetic studies, but during the culture period, GABAa receptors are likely to undergo different modulatory processes. In this study, the current responses to ultrafast GABA applications were recorded from patches excised from neurons cultured for either up to two days (short-term culture) or for more than two weeks (long-term culture). The dose-dependencies of the currentrising phases revealed significant differences between the two groups. In the short-term cultures, the responses to both saturating and non-saturating GABA concentrations were slower than in the case of the long-term cultures. We conclude that the GABAa receptors in cultured neurons undergo profound kinetic changes involving the modulation of the binding reaction and transitions between bound states.
18
Content available remote

Influence of extracellular pH on the modulatory effect of zinc ions on Kv1.3 potassium channels

63%
Teisseyre A., Mozrzymas J. W.
Journal of Physiology and Pharmacology
|
2006
|
tom 57
|
nr 1
In the present study we applied the whole-cell patch-clamp technique to study the influence of extracellular pH (pHo) on the modulatory effect exerted by zinc ions (Zn2+) on voltage-gated potassium channels Kv1.3 expressed in human lymphocytes. Obtained data provide evidence that lowering of pHo from the 7.35 to 6.4 slowed significantly the current activation rate, shifted the activation midpoint by about 16 mV towards positive membrane potentials and reduced the current amplitude to about 0.55 of the control value. In contrast, raising the pHo from 7.35 to 8.4 did not affect significantly the activation midpoint and current amplitude. Application of Zn2+ in the concentration range from 100 µM to 1 mM at pHo=6.4 slowed additionally the activation rate, shifted the activation midpoint by about 20 mV towards positive membrane potentials and reduced the current amplitude in a concentration-dependent manner. The total effect exerted by Zn2+ and protons at pHo = 6.4 was more significant than the effect exerted by Zn alone. Both the magnitude of the shift and the degree of current inhibition by Zn2+ were independent on pHo in the range from 6.4 to 8.4. The data might suggest that the effects exerted by protons and zinc ions occur independently on each other and probably involve different mechanisms. Changing the holding potential from -90 mV to -60 mV at pHo=7.35 abolished the Zn2+-induced inhibition of the current amplitudes at concentrations below 300 µM. At pHo=6.4 the total inhibition caused by Zn2+ and protons was also diminished, however, a significant reduction was observed at 100 µM concentration. In contrast, changing the holding potential did not change the Zn2+- and proton-induced shift of the activation midpoint. Altogether, obtained data suggest that extracellular protons exert the modulatory effects that are additive to the effects exerted by Zn2+ on the channels. Possible physiological significance of these additive effects is discussed.
19

Extracellular potassium affects the inhibition of lymphocyte Kv1.3 channels by zinc

63%
Mozrzymas J. W., Teisseyre A.
Cellular and Molecular Biology Letters
|
2002
|
tom 07
|
nr Suppl.
20

Protons affect GABAA receptor gating by altering both preactivation and desensitization transitions

51%
Kisiel M., Jatczak M., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: GABAA receptors are essential for inhibitory transmission in the adult central nervous system. It has been demonstrated that protons are potent modulators of GABAARs. It is known that α1F64 residue – which plays a role in the receptor preactivation (Szczot et al. 2014) – is also involved in pH sensitivity (Huang et al. 2004). For this reason, we decided to examine whether preactivation transitions are affected by protons. METHODS: To this end we used patch-clamp technique with rapid exchange system, and tested the impact of pH changes on macroscopic and single-channel currents evoked by saturating concentration of full (GABA) or partial (P4S) agonist and mediated by wild type (α1β2γ2) receptors or by α1F64 leucine and cysteine mutants. RESULTS: Acidification (from pH 8.0 to 6.0) caused a significant increase in current amplitude for all used combinations of receptors and agonists. This effect was accompanied by slowing down of desensitization kinetics (especially for currents elicited by GABA in non-mutated). Surprisingly, protons differently influenced deactivation kinetics in WT and mutated receptors. Kinetic simulations suggest that the mechanism of GABAARs modulation by pH changes includes both modifications in preactivation and in one of the classical gating components (opening or desensitization). Single-channel recordings for non-mutated receptors and for cysteine mutants indicated no effect of pH changes on closing/opening transitions suggesting thus the lack of protons impact on channel efficacy. Moreover, we observed that acidification caused prolongation of bursts in WT receptors and the longest component of closure dwell times in cysteine mutants. CONCLUSION: We conclude that protons modulate GABAARs by the impact on gating transitions involving both preactivation and microscopic desensitization. This work has been supported by grant DEC-2013/11/B/NZ3/00983 of National Centre of Science and ministry grant Pbmn135.
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