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

Lan Yue, Michal Pawlowski, Shlomo S. Dellal, An Xie, Feng Feng, Thomas S. Otis, Karol S. Bruzik, Haohua Qian and David R. Pepperberg ()
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Lan Yue: University of Illinois at Chicago
Michal Pawlowski: University of Illinois at Chicago
Shlomo S. Dellal: University of California at Los Angeles
An Xie: University of Illinois at Chicago
Feng Feng: University of Illinois at Chicago
Thomas S. Otis: University of California at Los Angeles
Karol S. Bruzik: University of Illinois at Chicago
Haohua Qian: University of Illinois at Chicago
David R. Pepperberg: University of Illinois at Chicago

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract Photochemical switches represent a powerful method for improving pharmacological therapies and controlling cellular physiology. Here we report the photoregulation of GABAA receptors (GABAARs) by a derivative of propofol (2,6-diisopropylphenol), a GABAAR allosteric modulator, which we have modified to contain photoisomerizable azobenzene. Using α1β2γ2 GABAARs expressed in Xenopus laevis oocytes and native GABAARs 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 GABAARs by an allosteric ligand, and open new avenues for fundamental and clinically oriented research on GABAARs, a major class of neurotransmitter receptors in the central nervous system.

Date: 2012
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DOI: 10.1038/ncomms2094

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