Robust photoregulation of GABA(A) 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 photoregulation of GABA(A) receptors (GABA(A)Rs) by a derivative of propofol (2,6-diisopropylphenol), a GABA(A)R allosteric modulator, which we have modified to contain photoisomerizable 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 γ-aminobutyric acid-elicited response and, at higher concentrations, directly activates the receptors. cis-MPC088, generated from trans-MPC088 by ultraviolet light (~365 nm), produces little, if any, receptor potentiation/activation. In cerebellar slices, MPC088 co-applied with γ-aminobutyric acid affords bidirectional photomodulation of Purkinje cell membrane current and spike-firing rate. The findings demonstrate photocontrol 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.
PubMed ID: 23033071
Article link: Nat Commun.
Grant support: AA01973 NIAAA NIH HHS , EY001792 NEI NIH HHS , EY016094 NEI NIH HHS , UL1RR029879 NCRR NIH HHS , UL1 RR029879 NCRR NIH HHS , P30 EY001792 NEI NIH HHS , R01 EY016094 NEI NIH HHS , R21 AA019737 NIAAA NIH HHS