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.
Mature retinal rod photoreceptors sequester opsin in the disk and plasma membranes of the rod outer segment (ROS) . Opsin is synthesized in the inner segment and is transferred to the outer segment along the connecting cilium that joins the two compartments . We have investigated early stages of retinal development during which the polarized distribution of opsin is established in the rod photoreceptor cell. Retinas were isolated from newborn rats, 3-21 d old, and incubated with affinity purified biotinyl-sheep anti-bovine opsin followed by avid in-ferritin . At early postnatal ages prior to the development of the ROS, opsin is labeled by antiopsin on the inner segment plasma membrane . At the fifth postnatal day, as ROS formation begins opsin was detected on the connecting cilium plasma membrane . However, the labeling density of the ciliary plasma membrane was not uniform : the proximal cilium was relatively unlabeled in comparison with the distal cilium and the ROS plasma membrane. In nearly mature rat retinas, opsin was no longer detected on the inner segment plasma membrane . A similar polarized distribution of opsin was also observed in adult human rod photoreceptor cells labeled with the same antibodies. These results suggest that some component(s) of the connecting cilium and its plasma membrane may participate in establishing and maintaining the polarized distribution of opsin.Development and maintenance of cell polarity is a crucial function of neuronal and epithelial cells . The specific distribution of membrane components to one or more surfaces of the cell may arise as a result of localized synthesis, vectorial transport of newly synthesized molecules from sites of synthesis to sites of function, localized reorganization of membrane components by translation along the membrane, or by redistribution of discrete portions of the cell membrane after insertion into the plasma membrane (15,17,20,22) . Visual cells of the vertebrate retina are highly compartmentalized and serve as a useful model for the study of the biogenesis of polarized membrane protein distribution. A unique photosensitive membranous organelle at one end of the cell, the rod outer segment (ROS)' has membranes composed largely of 'Abbreviations used in this paper: AvF, avidin-ferritin ; IMP, intramembranous particle ; PE, pigment epithelium ; RIS, rod inner segment ; ROS, rod outer segment. 1788 the integral membrane protein rhodopsin . Early biochemical studies and more recent immunocytochemical studies of mammalian and amphibian rod photoreceptors using antiopsin antibodies have demonstrated that the distribution of opsin is highly polarized : the disks and plasma membrane of the ROS contain abundant opsin whereas the inner segment is nearly unlabeled by antiopsin and contains little spectroscopically detectable rhodopsin (17,26).Polarity of opsin's distribution is maintained throughout adult life while the photoreceptor cell continuously renews the ROS membranes. Synthesis of opsin is confined to the rod inner segment (RIS) ...
The retinal degeneration slow or rds gene encodes rds/peripherin, an integral membrane glycoprotein in the outer segments of rod and cone photoreceptors. Mice homozygous for a null mutation in rds fail to develop outer segments and undergo subsequent degeneration of photoreceptors by the apoptotic pathway. Mutations in the human RDS gene are responsible for several forms of inherited blindness including autosomal-dominant retinitis pigmentosa and macular degeneration. Here, we examined the effects of ectopic Bcl-2 expression in transgenic photoreceptors on the rate of retinal degeneration in rds mutant mice. We observed an approximately twofold preservation of photoreceptors compared with nontransgenic rds mutant mice at 3 months. Immunoblot analysis showed similar levels of Bcl-2 in 2-, 3-, and 4-week-old transgenic mice. Expression of Bcl-2 in the rds mouse did not lead to outer segment formation and did not induce cell death. These results suggest that Bcl-2 expression may be an effective therapeutic strategy in humans with mutations in RDS or other genes that affect the integrity of photoreceptor outer segments.
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