Robust photoregulation of GABAA receptors by allosteric modulation with a propofol analogue

Photochemical switches represent a powerful method for improving pharmacological therapies and controlling cellular physiology. Here we report the photo-regulation of GABA(A) receptors (GABA(A)Rs) by a derivative of propofol (2,6-diisopropylphenol), a GABA(A)R allosteric modulator, that we have modified to contain photo-isomerizable azobenzene. Using α(1)β(2)γ(2) GABA(A)Rs expressed in Xenopus laevis oocytes and native GABA(A)Rs of isolated retinal ganglion cells, we show that the trans-azobenzene isomer of the new compound (trans-MPC088), generated by visible light (wavelengths ~440 nm), potentiates the GABA-elicited response and at higher concentrations directly activates the receptors. cis-MPC088, generated from trans-MPC088 by UV light (~365 nm), produces little if any receptor potentiation/activation. In cerebellar slices, MPC088 co-applied with GABA affords bidirectional photo-modulation of Purkinje cell membrane current and spike-firing rate. The findings demonstrate photo-control of GABA(A)Rs by an allosteric ligand and open new avenues for fundamental and clinically oriented research on GABA(A)Rs, a major class of neurotransmitter receptors in the central nervous system