Abstract
Pentameric ligand gated ion channels (pLGICs) mediate fast neurotransmission in the central and peripheral nervous systems. Modulators such as lipids, alcohols and general anesthetics allosterically modify the conformations of pentameric ligand gated ion channels (pLGICs) via the transmembrane domain. However, the molecular mechanisms underlying modulation are still unclear. GLIC is a prokaryotic homologue that has an overall conserved architecture and high sensitivity to clinically relevant compounds as the eukaryotic members of the family. Our study probed the functional and structural effect of acyl chain length and degree of unsaturation of polyunsaturated fatty acids (PUFAs) on GLIC function. A novel binding site for PUFAs on GLIC and the effect of perturbations on this site were investigated. By using a combination of electrophysiology, EPR spectroscopy, and X-ray crystallography we show a possible mechanism of PUFA modulation of pLGIC function through coupling of the outermost M4 helix with the channel pore.
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