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Hongyan Li, Zhijing Zhang, Christophe P. Ribelayga, Steven W. Wang, Michael R. Blackburn, John O'Brien; Dopamine And Adenosine Coordinately Regulate Photoreceptor Gap Junction Phosphorylation And Coupling. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5266.
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Photoreceptors are well coupled to each other through connexin 36 (Cx36) gap junctions. This coupling undergoes prominent changes through the day/night cycle and is controlled by phosphorylation of Cx36. Both phosphorylation level and photoreceptor coupling are high at night in darkness and low in the daytime under light exposure. Activation of protein kinase A (PKA) phosphorylates Cx36 and increases photoreceptor coupling in daytime under light exposure. Retinal dopamine and adenosine levels display opposing light/dark rhythms and both antagonistically regulate intracellular cAMP level. We therefore examined the ability of dopamine and adenosine receptors to control photoreceptor gap junction phosphorylation and, by inference, photoreceptor coupling in mouse retina.
Adult C57BL/6 and adenosine receptor A2a knockout (A2a-/-) mice were maintained under a 12h light/dark cycle. Dopamine and adenosine receptors were localized in retina by in situ hybridization. Isolated eyecup system was examined under light exposure or in darkness. Phosphorylation level was evaluated by immunolabeling using antibodies for phospho-Cx36 and pan-Cx36. Dopamine release was examined by means of HPLC.
In situ hybridization showed that D4 receptors were expressed in photoreceptors and a few cells in the ganglion cell layer. A2a receptors were expressed in the inner nuclear layer and weakly in photoreceptors. Both transcripts showed prominent changes in expression with time of day. Cx36 phosphorylation in photoreceptors was increased by dark adaptation and decreased by light adaptation. Inhibiting D4 or activating A2a receptors elevated phosphorylation in the light-adapted retina. These increases were blocked by a PKA antagonist, suggesting that dopamine and adenosine modulate coupling by changing PKA activity. In A2a-/- mice, Cx36 phosphorylation was surprisingly high in light but did not increase in darkness and was not enhanced by adenosine receptor agonist CGS-21680. In A2a-/- mice the level of dopamine release was constantly reduced in daytime light and darkness.
Both dopamine and adenosine receptors play direct roles in regulating Cx36 phosphorylation by controlling PKA activity in the photoreceptor, indicating that dopamine and adenosine control photoreceptor coupling in an opposite way. In addition, adenosine may also regulate dopamine secretion in the inner retina.
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