Linking agonist binding to GABAA receptor opening transition

• Autorzy: Morrzymas J.W. , Kisiel M. , Jatczak M. , Czyzewska M. , Brodzki M.
• Języki publikacji: EN

Abstrakty

EN

GABAA receptors are responsible for mediating inhibition in the adult mammalian CNS. These receptors are greatly diversified but the most common type is alpha1beta2gamma2. Intriguingly, GABA binding sites on GABAA receptor are remarkably distant (ca. 5 nm) from the channel gate. This structural feature raises the question about molecular mechanisms underlying the energy transfer from binding process to conformational transitions. Recently, we found that mutation of binding site residue alpha1F64 affects not only binding but also conformational transitions. Extensive experimental data and model simulations indicated that the major mechanism underlying alpha1F64 mutation is to affect so called preopening (channel remains closed but increases its propensity to open) and desensitization (Szczot et al. 2014). Singlechannel revealed that, additionally, this mutation shortens the channel opening time, indicating increase in the closing rate. Interestingly, alpha1F64 mutation was found to affect GABAAR proton sensitivity (Huang et al. 2004). We thus checked the impact of pH changes on WT and mutated alpha1beta2gamma2 receptors and found that protons modulate gating by altering mainly preactivation and desensitization. Kinetic analysis of alpha1beta2gamma2 receptors with mutation at a different location within agonist binding site (beta2E155) suggested again involvement of this residue in preactivation transition. Taking altogether, preactivation transition emerges as a key conformation transition which affects both kinetics and pharmacological sensitivity of currents mediated by alpha1beta2gamma2 GABAA receptors. Supported by NCN grant DEC-2013/11/B/NZ3/00983.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2015
• Tom: 75
• Numer: Supl.
• Opis fizyczny: p.S31

Twórcy

autor

Morrzymas 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

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

Czyzewska M.

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

autor

Brodzki 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