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N. Pozdeyev, M. T. Pardue, L. Li, R. H. Lee, P. M. Iuvone; Dopamine Regulates Phosducin/Transducin Interactions in Mouse Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4646.
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Phosducin (Pdc) is a regulatory phosphoprotein abundantly expressed in retinal photoreceptors. Pdc is phosphorylated in darkness and dephosphorylated following light exposure. Dephosphorylated Pdc binds to transducin ßγ (Gtßγ) subunits, causing their solubilization and translocation within photoreceptor cell compartments. We found that dopamine regulates diurnal and circadian rhythms in phosducin phosphorylation by binding to D4 receptors that negatively couple to adenylyl cyclase and inhibit cAMP formation. In this study we investigated the effect of D4 receptor activation on Pdc/ Gtß interactions and outer retinal function using the electroretinogram (ERG).
Experiments were performed on wild type and dopamine D4 receptor knock-out mice on a C57Bl/6 background. Pdc phosphorylation was quantified by immunoblotting with phosphospecific (pSer-71) and pan-phosducin antibodies. Pdc/Gtß interactions were studied using semi-quantitative co-immunoprecipitation with Gtß antibodies. Dark-adapted ERGs were recorded to full-field stimuli and a- and b-wave amplitudes measured.
D2/D4 dopamine receptor agonists, quinpirole and PD168077, induced Pdc dephosphorylation and significantly increased Pdc/Gtß binding in dark-adapted retinas from wild type, but not D4 receptor knock-out, mice. At least 40% of total Gtß bound to Pdc as a result of dopamine D4 receptor activation or exposure to light. The D4-selective dopamine receptor agonist PD168077 reduced scotopic ERG a- and b-wave amplitudes and oscillatory potentials.
Activation of D4 receptors promotes Pdc dephosphorylation, Pdc/Gtß complex formation, and reduction in ERG a- and b-waves, which may reflect a novel mechanism for neuromodulation of G-protein signaling in photoreceptors. The relationship between the effects of D2/D4 agonists on Pdc/Gtß binding and ERG responses requires further investigation.
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