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

• Autorzy: Michalowski M.A. , Mozrzymas J.W.
• Języki publikacji: EN

Abstrakty

EN

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.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2019
• Tom: 79
• Numer: Suppl.1
• Opis fizyczny: p.LXXXV-LXXXVI

Twórcy

autor

Michalowski M.A.

• Department of Molecular Physiology and Neurobiology, University of Wroclaw, Wroclaw, Poland

autor

Mozrzymas J.W.

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