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 (D₄R) affects a light-sensitive pool of cyclic AMP by negatively coupling to the type 1 adenylyl cyclase (AC1). AC1 is the primary enzyme controlling cyclic AMP production in dark-adapted photoreceptors. A previous study demonstrated that expression of the gene encoding AC1, Adcy1, is downregulated in mice lacking Drd4, the gene encoding the D₄R. The present investigation provides evidence that D₄R 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 AC activity and cyclic AMP levels were observed. However, these rhythmic activities were damped or undetectable in mice lacking the D₄R. Pharmacologically activating the D₄R 4 h 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 D₄R is essential in maintaining the normal rhythmic production of AC1 from transcript to enzyme activity. Thus, dopamine/D₄R signaling is a novel zeitgeber that entrains the rhythm of Adcy1 expression and, consequently, modulates the rhythmic synthesis of cyclic AMP in mouse retina.