Robust photoregulation of GABAA receptors byallosteric modulation with a propofol analogue

摘要

Photochemical switches represent a powerful method for improving pharmacologicaltherapies and controlling cellular physiology. Here we report the photoregulation of GABAAreceptors (GABAARs) by a derivative of propofol (2,6-diisopropylphenol), a GABAAR allostericmodulator, which we have modified to contain photoisomerizable azobenzene. using alpha 1beta 2 gamma 2GABAARs expressed in Xenopus laevis oocytes and native GABAARs of isolated retinal ganglioncells, we show that the trans-azobenzene isomer of the new compound (trans-mPC088),generated by visible light (wavelengths -440 nm), potentiates the gamma-aminobutyric acidelicited response and, at higher concentrations, directly activates the receptors. cis-mPC088,generated from trans-mPC088 by ultraviolet light (-365 nm), produces little, if any, receptorpotentiation/activation. In cerebellar slices, mPC088 co-applied with gamma-aminobutyric acidaffords bidirectional photomodulation of Purkinje cell membrane current and spike-firingrate. The findings demonstrate photocontrol of GABAARs by an allosteric ligand, and opennew avenues for fundamental and clinically oriented research on GABAARs, a major class ofneurotransmitter receptors in the central nervous system.