Dysfunctional Light-Evoked Regulation of cAMP in Photoreceptors and Abnormal Retinal Adaptation in Mice Lacking Dopamine D4 Receptors

Abstract

Dopamine is a retinal neuromodulator that has been implicated in many aspects of retinal physiology. Photoreceptor cells express dopamine D4 receptors that regulate cAMP metabolism. To assess the effects of dopamine on photoreceptor physiology, we examined the morphology, electrophysiology, and regulation of cAMP metabolism in mice with targeted disruption of the dopamine D4 receptor gene. Photoreceptor morphology and outer segment disc shedding after light onset were normal in D4 knock-out (D4KO) mice. Quinpirole, a dopamine D2/D3/D4 receptor agonist, decreased cAMP synthesis in retinas of wild-type (WT) mice but not in retinas of D4KO mice. In WT retinas, the photoreceptors of which were functionally isolated by incubation in the presence of exogenous glutamate, light also suppressed cAMP synthesis. Despite the similar inhibition of cAMP synthesis, the effect of light is directly on the photoreceptors and independent of dopamine modulation, because it was unaffected by application of the D4 receptor antagonist l-745,870. Nevertheless, compared with WT retinas, basal cAMP formation was reduced in the photoreceptors of D4KO retinas, and light had no additional inhibitory effect. The results suggest that dopamine, via D4 receptors, normally modulates the cascade that couples light responses to adenylyl cyclase activity in photoreceptor cells, and the absence of this modulation results in dysfunction of the cascade. Dark-adapted electroretinogram (ERG) responses were normal in D4KO mice. However, ERG b-wave responses were greatly suppressed during both light adaptation and early stages of dark adaptation. Thus, the absence of D4 receptors affects adaptation, altering transmission of light responses from photoreceptors to inner retinal neurons. These findings indicate that dopamine D4 receptors normally play a major role in regulating photoreceptor cAMP metabolism and adaptive retinal responses to changing environmental illumination.

Function of phosducin-like proteins in G protein signaling and chaperone-assisted protein folding

“…In the dark when cAMP levels in photoreceptors are high [33,34], Pdc is phosphorylated and thus would not compete with G t α for G t βγ binding. In the light, cAMP levels in photoreceptors fall [33,34], resulting in Pdc dephosphorylation and disruption of the binding of G t α to G t βγ. This G t βγ sequestration hypothesis has influenced thinking about the function of Pdc in the retina for some time and additional evidence has accumulated over time in support of its premises.…”

HCN4-like immunoreactivity in rat retinal ganglion cells

“…In this respect, HCN4 channels are interesting to investigate because their voltage sensitivity is altered to a greater extent by cAMP than in any of the other mammalian HCN isoforms (e.g., Ludwig et al, 1998;Santoro et al, 2000). This would predict that the contribution of I h to resting membrane potential and resistance (Lee and Ishida, 2007) and to rebound excitation (Tabata and Ishida, 1996;Lee et al, 2003;Lee and Ishida, 2007) is increased by conditions that elevate intracellular cAMP levels (Vaquero et al, 2001;Nir et al, 2002;Dunn et al, 2006;Mills et al 2007). However, properties of the net current are shaped by the presence of other HCN isoforms (Franz et al, 2000;Santoro et al, 2000;Altomare et al, 2001;Chen et al, 2001).…”

Connexin 35/36 is phosphorylated at regulatory sites in the retina

“…The effect of light on photoreceptors is partially mimicked by dopamine D2/D4-like receptor activation (Krizaj et al, 1998), which results in reduction of adenylyl cyclase activity and cytoplasmic cAMP concentration (Cohen et al, 1992;Nir et al, 2002). In other retinal networks, the opposite effect is mediated by dopamine D1-type receptors.…”