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Ignacio Sarria, Yan Cao, Kirill A Martemyanov; Sensitivity and kinetics of GPCR signaling in rod to ON-bipolar synaptic transmission differentially control visually guided behavior. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4168.
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Transmission of the light signal from rods to downstream ON-bipolar cells (ON-BC) is essential for dim vision and dysfunctions in components of this signaling pathway have been shown to cause night blindness in humans. In ON-BC the signaling is mediated by the G protein signal transduction, where the mGluR6 receptor constantly stimulated in the dark by glutamate activates Go and closes the TRPM1 channel. We have shown that RGS7 and RGS11 control Go deactivation and their complete knockout in mice eliminates ON-BC responses to light-flashes. Here we study the effect of progressive RGS loss to the light- responses of ON-BC cells and visual performance in mice.
We generated a novel inducible RGS7 knockout by crossing RGS7flx/flx mice on RGS11 KO background (RGS11-/-:RGS7 flx/flx) with the driver line ubiquitously expressing tamoxifen-inducible Cre-ERT2 recombinase to produce RGS11-/-:RGS7 flx/flx:CAG CreERT2 (cDKO mice). RGS7 elimination was induced tamoxifen gavage. Protein expression, quantification, and localization where analyzed by western blotting and immunohistochemistry respectively. Light-evoked responses were studied by ERG. Mouse visual behavior was assessed using a water maze task with a visible escape platform.
Gradual elimination of RGS in ON-BC results in a new and progressively deteriorating b-wave phenotype. Decreases in RGS7 concentration reduced the amplitude, sensitivity and slowed onset kinetics. Additionally, scotopic visual performance worsens as RGS7 abundance drops, ending in complete nigh-blindness. Based on quantification of RGS7 levels we correlated major parameters of the b-wave with performance in behavioral task. We observed amplitude, sensitivity and onset kinetics were differentially impacted by RGS concentration loss. The b-wave amplitude and onset kinetics were more readily affected, decreasing with smaller reductions in RGS concentration. In contrast, changes in response sensitivity required greater reduction in RGS7 levels. Interestingly behavioral performance was strictly correlated with changes in response sensitivity rather than amplitude or kinetics.
We conclude that different parameters of ON-BC cell response are tuned to different concentration ranges of RGS proteins. However, ultimately visual behavior requires high sensitivity of the synaptic transmission at the first visual synapse.
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