Dopamine D4 receptor activation controls circadian timing of the adenylyl cyclase 1/cyclic AMP signaling system in mouse retina

In the mammalian retina, dopamine binding to the dopamine D4 receptor affects a light-sensitive pool of cyclic AMP by negatively coupling to the type 1 adenylyl cyclase. The type 1 adenylyl cyclase is the primary enzyme controlling cyclic AMP production in dark-adapted photoreceptors. A previous study demonstrated that expression of the gene encoding the type 1 adenylyl cyclase, Adcy1, is down regulated in mice lacking Drd4, the gene encoding the dopamine D4 receptor. The present investigation provides evidence that dopamine D4 receptor activation entrains the circadian rhythm of Adcy1 mRNA expression. Diurnal and circadian rhythms of Drd4 and Adcy1 mRNA levels were observed in wild type mouse retina. Also, rhythms in the Ca2+-stimulated adenylyl cyclase activity and cyclic AMP levels were observed. However, these rhythmic activities were damped or undetectable in mice lacking the dopamine D4 receptor. Pharmacologically activating the dopamine D4 receptor 4 hrs before its normal stimulation at light onset in the morning advances the phase of the Adcy1 mRNA expression pattern. These data demonstrate that stimulating the dopamine D4 receptor is essential in maintaining the normal rhythmic production of the type 1 adenylyl cyclase from transcript to enzyme activity. Thus, dopamine/dopamine D4 receptor signaling is a novel zeitgeber that entrains the rhythm of Adcy1 expression and, consequently, modulates the rhythmic synthesis of cyclic AMP in mouse retina.