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

Author

Listed:
  • Lan Yue

    (University of Illinois at Chicago
    University of Illinois at Chicago)

  • Michal Pawlowski

    (University of Illinois at Chicago)

  • Shlomo S. Dellal

    (University of California at Los Angeles
    Present address: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine at Yeshiva University, Rose F. Kennedy Center, 1410 Pelham Parkway South, Bronx, New York 10461, USA.)

  • An Xie

    (University of Illinois at Chicago
    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
    Present address: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine at Yeshiva University, Rose F. Kennedy Center, 1410 Pelham Parkway South, Bronx, New York 10461, USA.)

  • David R. Pepperberg

    (University of Illinois at Chicago
    University of Illinois at Chicago)

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.

Suggested Citation

  • Lan Yue & Michal Pawlowski & Shlomo S. Dellal & An Xie & Feng Feng & Thomas S. Otis & Karol S. Bruzik & Haohua Qian & David R. Pepperberg, 2012. "Robust photoregulation of GABAA receptors by allosteric modulation with a propofol analogue," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2094
    DOI: 10.1038/ncomms2094
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