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H. Li, S. W. Wang, C. Ribelayga, J. O'Brien; Connexin36 Phosphorylation is Regulated by Dopamine and Adenosine in Mouse Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6427.
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Photoreceptors are coupled by connexin 36 gap junctions and undergo prominent changes in coupling through the day/night cycle, with strong coupling at night and weak coupling in the day or when light-adapted. We have shown that photoreceptor coupling is directly correlated to Cx35 (homologous to Cx36) phosphorylation in zebrafish. Dopamine and adenosine display opposing circadian rhythms in the retina and are important modulators of retinal function. In this study, we examine the ability of dopamine and adenosine receptors to control photoreceptor gap junction phosphorylation and by inference, coupling, in mouse retina.
Adult wild-type (C57/Bl6) female mice were maintained under a 12 h light:12 h dark cycle. Experiments were conducted during daytime, 4-6h after light onset, under dark-adapted conditions following 2 h of dark adaptation (control) or under light-adapted conditions (control and drugs). Isolated eyecups were incubated in oxygenated Ames’ medium alone (control) or supplemented with the D4 receptor antagonist L-745870 or the A2a receptor agonist CGS-21680 for 30 min. Phosphorylation at Ser293 of Cx36 was evaluated by immunostaining with antibodies against phosphoSer293 and Cx36 and expressed as the ratio of phospho-antibody to Cx36 antibody labeling intensity in the outer plexiform layer (OPL).
Under light-adapted conditions, Cx36 gap junctions in the mouse OPL were poorly phosphorylated, as was previously seen in zebrafish. Two hour dark adaptation slightly increased the phosphorylation level. However, application of L-745870 or CGS-21680 under light-adapted conditions each led to extensive phosphorylation in the OPL.
Mouse photoreceptor gap junctions undergo changes in phosphorylation state associated with dark and light adaptation. The daytime state can be reversed by inhibition of dopamine D4 receptors or activation of adenosine A2a receptors. This supports a model in which adenosine and dopamine co-regulate the pathway that controls photoreceptor coupling. This pathway may work via adenylyl cyclase activation/inhibition, with adenosine providing the nighttime signal to phosphorylate gap junctions and dopamine providing the daytime signal to suppress phosphorylation.
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