title: Robust photoregulation of GABA(A) receptors by allosteric modulation with a propofol analogue.
abstract: 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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 West Taylor Street, Chicago, Illinois 60612, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Yue
authors.forename: Michal
authors.initials: M
authors.lastname: Pawlowski
authors.forename: Shlomo S
authors.initials: SS
authors.lastname: Dellal
authors.forename: An
authors.initials: A
authors.lastname: Xie
authors.forename: Feng
authors.initials: F
authors.lastname: Feng
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Otis
authors.forename: Karol S
authors.initials: KS
authors.lastname: Bruzik
authors.forename: Haohua
authors.initials: H
authors.lastname: Qian
authors.forename: David R
authors.initials: DR
authors.lastname: Pepperberg
mesh_terms: D000494:Allosteric Regulation / Q000528:radiation effects*; D000818:Animals; D001391:Azo Compounds / Q000737:chemistry; D004594:Electrophysiology; D005260:Female; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015742:Propofol / Q000737:chemistry / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid
chemical_list: D001391:Azo Compounds; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C009850:azobenzene; D015742:Propofol