Essential roles of dopamine D₄ receptors and the type 1 adenylyl cyclase in photic control of cyclic AMP in photoreceptor cells

Abstract

Dopamine is a neuromodulator that influences many physiological functions in the retina (reviewed by Witkovsky 2004). It enhances cone input signals and decreases rod input signals, uncouples horizontal cell and AII amacrine cell gap junction networks, enhances contrast sensitivity, and modulates light-and dark-adaptation. Also, it has trophic actions within the retina, affecting circadian rhythms, retinal development, and ocular growth (Witkovsky 2004). Activation of dopamine receptors, particularly the dopamine D 4 receptor (D 4 R) subtype from the D 2 family of receptors, suppresses the light-sensitive pool of cyclic AMP in dark-adapted mouse photoreceptors (Cohen and Blazynski 1990;Cohen et al. 1992). Cyclic AMP levels in photoreceptor cells are highest in darkness and reduced by light exposure. Although it is known that light and D 4 R activation regulate the same pool of cyclic AMP, they appear to do so by different mechanisms. Nir et al. (2002) showed that the effect of light is not directly dependent on D 4 R activation; however, in mice lacking D 4 Rs (Drd4)/) mice), cyclic AMP levels were significantly lower in darkness and unresponsive to light when compared with wild-type controls. These observations suggested that D 4 R activation Similarly, in mice with disruption of the gene (Drd4) encoding D 4 R, cyclic AMP levels in the dark-adapted retina are significantly lower compared to wild-type retina and are unresponsive to light. These changes in Drd4)/) mice were accompanied by significantly lower Adcy1 mRNA levels in photoreceptor cells and lower Ca 2+ /calmodulin-stimulated adenylyl cyclase activity in retinal membranes compared with wild-type controls. Reduced levels of Adcy1 mRNA were also observed in retinas of wild-type mice treated chronically with a D 4 R antagonist, L-745870. Thus, activation of D 4 R is required for normal expression of AC1 and for the regulation of its catalytic activity by light. These observations illustrate a novel mechanism for cross-talk between dopamine and photic signaling pathways regulating cyclic AMP in photoreceptor cells.

The Retina and Other Light-sensitive Ocular Clocks

“…Furthermore, dopamine appears to contribute to light induced phase shifts as they are reduced by DRD1 antagonists (Figure 4). The phase shifting effects of dopamine on the PER2 ∷luc rhythm also contrasts with dopamine's direct regulatory drive of circadian rhythms of ADCY1 , cAMP and melatonin synthesis in photoreceptors (Fukuhara et al, 2004, Jackson et al, 2011, Jackson et al, 2009). Here the rhythms appear to be driven tonically by dopamine occupancy of DRD4 receptors.…”

Dopamine signaling and myopia development: What are the key challenges

“…Consistent with volume transmission of DA, DA receptors are found on almost all neuronal classes within the retina. The retina expresses 4 of the 5 DA receptor subtypes: D 1 R, D 2 R, D 4 R, and D 5 R (Table 1; (Jackson et al, 2009)). D 1 and D 5 receptors stimulate the synthesis of the intracellular second messenger cyclic AMP, while D 2 and D 4 receptors inhibit its formation (Beaulieu and Gainetdinov, 2011).…”

The Retinal Clock Drives the Expression ofKcnv2, a Channel Essential for Visual Function and Cone Survival

“…16,17 Daily adaptation of the retina is driven by the retina's own circadian clock system, [18][19][20] which consists of component clocks localized in various types of retinal cells, 21,22 including photoreceptor cells. [23][24][25] Little is known about the way in which the retinal clock system promotes the adaptation of visual function, except that clock-dependent formation of melatonin [26][27][28] and dopamine 29,30 would appear to play a role. With respect to melatonin formation, the clock system promotes a nocturnal increase in the formation of the hormone via the transcriptional activation of the gene arylalkylamine Nacetyltransferase (Aanat).…”