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Lan Yue, Michal Pawlowski, Karol Bruzik, David Pepperberg; Potentiation of bipolar cell GABAA receptors by a photo-isomerizable compound. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1761.
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Photochemical switches that regulate the activity of postsynaptic membrane receptors of inner retinal neurons represent a possible approach to vision restoration in photoreceptor degenerative diseases such as age-related macular degeneration. MPC088, a propofol analog that incorporates a photo-isomerizable azobenzene group, exhibits isomer-specific and thus photo-controllable potentiation of GABAA receptors of retinal ganglion cells (ref. 1). In the present study we asked whether GABAA receptors of retinal bipolar cells (RBCs) exhibit controllability by MPC088.
Single, isolated RBCs were prepared from retinas of 6-16 week-old Sprague-Dawley rats (1,2) and identified by cell morphology. Membrane currents were recorded by whole-cell voltage clamp (3). Trans-MPC088, the isomer with pronounced activity at ganglion cells (1), was converted to the cis-isomer by exposure to UV light (wavelengths near 365 nm) (1). Ringer solution containing GABA and trans- or cis-MPC088 was presented to the RBC by gravity-driven superfusion. Test solutions also contained TPMPA to inhibit RBC GABAA-ρ (GABAC) receptors.
Trans-MPC088 exhibited robust concentration-dependent potentiation of RBC GABAA receptors. With co-applied 100 μM TPMPA, 5 μM trans-MPC088 produced an ~1.7-fold enhancement of the GABAA component of the 10 μM GABA response (n=3). The potentiation factor increased to ~2.4-fold with 30 μM trans-MPC088 (n=9), and the potentiated GABA response was nearly eliminated by picrotoxin (100 μM), a GABAA channel blocker (~95% inhibition, n=3). UV-illuminated (thus, cis-dominant) 30 μM MPC088 produced a potentiation (~1.3-fold, n=5) significantly lower (p=0.0003) than that determined with the trans-isomer.
MPC088 exhibits isomer-dependent potentiation of RBC GABAA receptors, offering the possibility of photo-control at a post-photoreceptor stage presynaptic to ganglion cells (4). The results encourage development of MPC088-like structures that possess optimized wavelength sensitivity and relaxation kinetics, and that, via an incorporated affinity reagent, can target GABAA receptors on specific retinal cell types. (1) Yue et al. (2012) Nature Comm. 3:1095 (doi: 10.1038.ncomms2094). (2) Ramsey et al. (2007) Exper. Eye Res. 85:413-422. (3) Yue et al. (2011) Invest. Ophthalmol. Vis. Sci. 52:2497-2509. (4) Lagali et al. (2008) Nature Neurosci. 11:667-675.
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