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

• Autorzy: Kisiel M. , Jatczak M. , Mozrzymas J.W.
• Języki publikacji: EN

Abstrakty

EN

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.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2015
• Tom: 75
• Numer: Supl.
• Opis fizyczny: p.S108-S109

Twórcy

autor

Kisiel M.

• Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Wroclaw, Poland

autor

Jatczak M.

• Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Wroclaw, Poland
• Laboratory of Cellular Neurobiology, Department of Animal Molecular Physiology, Wroclaw University, Wroclaw, Poland

autor

Mozrzymas J.W.

• Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Wroclaw, Poland
• Laboratory of Cellular Neurobiology, Department of Animal Molecular Physiology, Wroclaw University, Wroclaw, Poland