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Lan Yue, Michal Pawlowski, Karol S. Bruzik, Haohua Qian, David R. Pepperberg; Direct Activation of GABAA Receptors of Retinal Ganglion Cells by a Propofol-based Photoisomerizable Compound. Invest. Ophthalmol. Vis. Sci. 2012;53(14):279.
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© ARVO (1962-2015); The Authors (2016-present)
Using light-regulated pharmacological agents to make inner retinal cells light-sensitive is a potential therapeutic approach in retinal diseases that involve loss/dysfunction of native rods and cones. Propofol, a widely used anesthetic, is a known allosteric modulator of GABAA receptors (GABAARs). We have recently developed "MPC088", a propofol derivative modified to contain a photoisomerizable azobenzene group. In trans isomer form, MPC088 exhibits robust potentiation of the GABA-elicited response on heterologously expressed and native GABAARs (refs.1-3). By contrast, the cis isomer of MPC088 generated by UV illumination exhibits little if any potentiating activity. A question of particular importance is whether MPC088, in addition to its potentiating activity, can itself directly activate GABAARs. Here we asked whether, as with GABAARs expressed on Xenopus oocytes, MPC088 directly activates ganglion cell GABAARs.
Solitary ganglion cells were obtained from enzymatically dissociated rat retina (Sprague-Dawley, 6-16 weeks); current responses were monitored by whole-cell voltage clamp recording. Test agents dissolved in Ringer were presented to the cell by superfusion. Cis isomer was generated from trans by exposure to UV light (1).
Trans-dominant MPC088 at 30 μM produced a small response whose peak amplitude was 5 ± 1% of that elicited by 200 μM GABA (n=3). However, at 60 μM, the agonist effect increased to 43 ± 9% of the 200 µM GABA-elicited response (n = 7). Pre-treatment of trans-dominant MPC088 with UV light, i.e., conversion of MPC088 to cis-dominant form, reduced this activity by 88 ± 6% (n = 4; p = 0.002). Trans-MPC088’s agonist activity was virtually eliminated by co-applied picrotoxin (100 μM), a GABAAR channel blocker.
MPC088 directly activates GABAARs of isolated retinal ganglion cells. As with the compound’s potentiation effect, direct activation by MPC088 depends strongly on its isomeric configuration, with the trans isomer active. The results raise the possibility of photo-controlling ganglion cell activity by allosteric GABAAR modulation even in the absence of native GABA neurotransmitter. (1) Yue et al., Soc. for Neurosci. 2010. (2) Xie et al., 2011 ARVO; (3) Yue et al., Soc. for Neurosci. 2011.
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