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Featured researches published by M Kisiel.


The Journal of Neuroscience | 2014

α1F64 Residue at GABAA Receptor Binding Site Is Involved in Gating by Influencing the Receptor Flipping Transitions

Marcin Szczot; M Kisiel; M M Czyzewska; Jerzy W. Mozrzymas

GABA receptors (GABAARs) mediate inhibition in the adult brain. These channels are heteropentamers and their ligand binding sites are localized at the β(+)/α(−) interfaces. As expected, mutations of binding-site residues affect binding kinetics but accumulating evidence indicates that gating is also altered, although the underlying mechanisms are unclear. We investigated the impact of the hydrophobic box residue localized at α1(−), F64 (α1F64), on the binding and gating of rat recombinant α1β1γ2 receptors. The analysis of current responses to rapid agonist applications confirmed a marked effect of α1F64 mutations on agonist binding and revealed surprisingly strong effects on gating, including the disappearance of rapid desensitization, the slowing of current onset, and accelerated deactivation. Moreover, nonstationary variance analysis revealed that the α1F64C mutation dramatically reduced the maximum open probability without altering channel conductance. Interestingly, for wild-type receptors, responses to saturating concentration of a partial agonist, P4S, showed no rapid desensitization, similar to GABA-evoked responses mediated by α1F64C mutants. For the α1F64L mutation, the application of the high-affinity agonist muscimol partially rescued rapid desensitization compared with responses evoked by GABA. These findings suggest that α1F64 mutations do not disrupt desensitization mechanisms but rather affect other gating features that obscure it. Model simulations indicated that all of our observations related to α1F64 mutations could be properly reproduced by altering the flipped state transitions that occurred after agonist binding but preceded opening. In conclusion, we propose that the α1F64 residue may participate in linking binding and gating by influencing flipping kinetics.


Molecular Biology of the Cell | 2016

CD44: a novel synaptic cell adhesion molecule regulating structural and functional plasticity of dendritic spines

Matylda Roszkowska; Anna Skupien; Tomasz Wójtowicz; Anna Konopka; Adam Gorlewicz; M Kisiel; Marek Bekisz; Blazej Ruszczycki; Hubert Dolezyczek; Emilia Rejmak; Ewelina Knapska; Jerzy W. Mozrzymas; Jakub Wlodarczyk; Grzegorz M. Wilczynski; Joanna Dzwonek

CD44 is a novel molecular player that regulates structure and function of the synapse. It affects excitatory synaptic transmission, dendritic spine shape, number of functional synapses, and activity-dependent neuronal plasticity. These functions are exerted via the regulation of small Rho GTPases.


European Journal of Pharmacology | 2016

Comparison of kinetic and pharmacological profiles of recombinant α1γ2L and α1β2γ2L GABAA receptors - A clue to the role of intersubunit interactions.

Marek Brodzki; Radoslaw Rutkowski; M Jatczak; M Kisiel; M M Czyzewska; Jerzy W. Mozrzymas

The fastest inhibitory mechanism in the CNS is mediated by ionotropic GABAA receptors and it is known that subunit composition critically determines their properties. While a typical GABAA receptor consists of two α, two β and one γ/δ subunit, there are some exceptions, e.g. αβ receptors. Functional α1γ2 GABAA receptors can be expressed in recombinant model (Verdoorn et al., 1990) and although their role remains unknown, it seems appealing to extend their characterization to further explore the structure-function relationship of GABAA receptors. Intriguingly, this receptor is lacking canonical GABA binding sites but it can be activated by GABA and dose-response relationships for α1β2γ2L and α1γ2L receptors overlap. Deactivation kinetics was similar for both receptors but the percentage of the fast component was smaller in the case of α1γ2L receptors and, consequently, the mean deactivation time constant was slower. The rate and extent of macroscopic desensitization were smaller in the case of α1γ2L receptors but they showed slower recovery. Both receptor types had a similar proton sensitivity showing only subtle but significant differences in pH effects on deactivation. Flurazepam exerted a similar effect on both receptors but the rapid deactivation components were differently affected and an opposite effect was observed on desensitization extent. Rebound currents evoked by pentobarbital were undistinguishable for both receptor types. Taking altogether, although some significant differences were found, α1β2γ2L and α1γ2L receptors showed unforeseen similarity. We propose that functioning of GABAA receptors might rely on subunit-subunit cooperative interactions to a larger extent than believed so far.


Neuropharmacology | 2017

Spontaneous activity, singly bound states and the impact of alpha 1 Phe64 mutation on GABA A R gating in the novel kinetic model based on the single-channel recordings

M Kisiel; M Jatczak; Marek Brodzki; Jerzy W. Mozrzymas

ABSTRACT GABAA receptor is the primary mediator of inhibition in the adult mammalian brain. Our recent studies revealed that a classic gating scheme for GABAAR needed to be updated with an intermediate step (flipping) and that the &agr;1Phe64 mutation at the GABA binding site affects this transition. However, description of flipping at the single‐channel level remains incomplete. In particular, its role in singly‐bound and spontaneous activity remains unknown. We have performed thus single‐channel recordings over wide range of agonist concentration for wild‐type &agr;1&bgr;2&ggr;2L receptors and &agr;1Phe64 mutants. For WT receptors we observed relatively frequent brief spontaneous openings which were also present at low [GABA]. However, closed times distributions for spontaneous activity and at low [GABA] were clearly different indicating that a proportion of short‐lived openings were due to liganded, most likely singly bound receptors. Increasing [GABA] resulted in prolongation of bursts and increased occurrence of bursts with long openings and short closures. Mutations of &agr;1Phe64 residue dramatically affected the open and closed time distributions at high and saturating [GABA], especially in the case of cysteine mutants. However, this mutation weakly affected spontaneous or singly bound activity. Model fitting of our single‐channel data led us to propose a novel and, to our knowledge, most complete GABAAR kinetic model in which flipping occurs in singly and doubly bound states. However, spontaneous activity did not reveal involvement of flipping. Moreover, we report that &agr;1Phe64 mutation affects not only the flipping but also the opening/closing transitions indicating its generalized impact on the receptor gating. HighlightsA novel and, to our knowledge, most complete GABAAR kinetic model is proposed.Activation via flipped state occurs for singly and doubly bound receptors.Spontaneous activity of GABAAR did not reveal involvement of flipping.&agr;1Phe64 mutations affect flipping but also the opening/closing transitions.


Neuropharmacology | 2018

Protons modulate gating of recombinant α1β2γ2 GABAA receptor by affecting desensitization and opening transitions

M Kisiel; Magdalena Jatczak-Śliwa; Jerzy W. Mozrzymas

ABSTRACT Protons are potent modulators of GABAA receptors (GABAARs) and &agr;1Phe64 residue was implicated in their pH sensitivity. Recently, we have demonstrated that this residue is involved in flipping transitions which precede channel opening. We thus re‐addressed the mechanism of GABAAR modulation by protons by considering the gating scheme extended by flipping. The impact of pH changes was examined on currents mediated by wild‐type &agr;1&bgr;2&ggr;2 receptors or by their &agr;1Phe64Leu or &agr;1Phe64Cys mutants and elicited by saturating concentrations of full (GABA) or partial (piperidine‐4‐sulfonic acid) agonists. To describe the impact of extracellular pH on receptor gating, we combined macroscopic analysis of currents elicited by rapid agonist applications with single‐channel studies. Acidification (pH 6.0) increased current amplitudes (in the case of leucine mutants effect was stronger when P4S was used) and decreased the rate and the extent of desensitization whereas alkalization (pH 8.0) had the opposite but weaker effect. Deactivation kinetics for wild‐type receptors was slowed down by acidification while in the case of mutants this effect was observed upon alkalization. Moreover, &agr;1Phe64 mutations enhanced GABAAR sensitivity to alkaline pH. Single‐channel analysis revealed that acidification prolonged burst durations and affected shut but not open time distributions. Model simulations for macroscopic and single‐channel activity indicated a novel mechanism in which protons primarily affected opening and desensitization rates but not flipping/unflipping. This evidence for the impact of protons on the receptor gating together with previously demonstrated effect on the agonist binding, point to a complex effect of extracellular pH on GABAAR macromolecule. HIGHLIGHTSExtracellular pH changes affect open probability of GABAA receptor.Protons affect GABAAR by altering primarily desensitization and opening rates.Flipping transitions appear not to be affected by pH changes.&agr;1Phe64 mutations enhance receptor sensitivity to alkalization.


Acta Neurobiologiae Experimentalis | 2015

Linking agonist binding to GABAA receptor opening transition

J W Morrzymas; M Kisiel; M Jatczak; M M Czyzewska; Marek Brodzki


Acta Neurobiologiae Experimentalis | 2015

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

M Kisiel; M Jatczak; Jerzy W. Mozrzymas


Acta Neurobiologiae Experimentalis | 2015

Different pharmacological profile in alpha1-gamma2 and alpha1-beta2-gamma2 GABAA receptors

M Brodzki; M M Czyzewska; R Rutkowski; M Kisiel; M Jatczak; J W Mozrzymas


Acta Neurobiologiae Experimentalis | 2015

GABAA receptor binding site residue Beta2 glutamate 155:possible role in channel preactivation

M Kisiel; M Jatczak; M M Czyzewska; Marek Brodzki; C Cajkowski; Jerzy W. Mozrzymas


Archive | 2014

Coupling Shape GABA-Evoked Currents Binding Sites, Singly Bound States, and Conformation

Jerzy W. Mozrzymas; Andrea Barberis; Katarzyna Mercik; Fabio Benfenati; Enrica Maria Petrini; Thierry Nieus; Tiziana Ravasenga; Stefania Guazzi; Marcin Szczot; M Kisiel; M M Czyzewska; Marcel P. Goldschen-Ohm; Alexander Haroldson; Mathew V. Jones; Robert A. Pearce

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M M Czyzewska

Wrocław Medical University

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Jerzy W. Mozrzymas

Wrocław Medical University

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M Jatczak

Wrocław Medical University

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Marcin Szczot

Wrocław Medical University

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Marek Brodzki

Wrocław Medical University

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Adam Gorlewicz

Nencki Institute of Experimental Biology

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Anna Konopka

Nencki Institute of Experimental Biology

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Anna Skupien

Nencki Institute of Experimental Biology

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Blazej Ruszczycki

Nencki Institute of Experimental Biology

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