Dopamine and full-field illumination activate D1 and D2-D5-type receptors in adult rat retinal ganglion cells
Department of Neurobiology, Physiology and Behavior, University of California, Davis, California 95616.The Journal of Comparative Neurology (Impact Factor: 3.23). 12/2012; 520(17):4032-49. DOI: 10.1002/cne.23159
Dopamine can regulate signal generation and transmission by activating multiple receptors and signaling cascades, especially in striatum, hippocampus, and cerebral cortex. Dopamine modulates an even larger variety of cellular properties in retina, yet has been reported to do so by only D1 receptor-driven cyclic adenosine monophosphate (cAMP) increases or D2 receptor-driven cAMP decreases. Here, we test the possibility that dopamine operates differently on retinal ganglion cells, because the ganglion cell layer binds D1 and D2 receptor ligands, and displays changes in signaling components other than cAMP under illumination that should release dopamine. In adult rat retinal ganglion cells, based on patch-clamp recordings, Ca(2+) imaging, and immunohistochemistry, we find that 1) spike firing is inhibited by dopamine and SKF 83959 (an agonist that does not activate homomeric D1 receptors or alter cAMP levels in other systems); 2) D1 and D2 receptor antagonists (SCH 23390, eticlopride, raclopride) counteract these effects; 3) these antagonists also block light-induced rises in cAMP, light-induced activation of Ca(2+) /calmodulin-dependent protein kinase II, and dopamine-induced Ca(2+) influx; and 4) the Ca(2+) rise is markedly reduced by removing extracellular Ca(2+) and by an IP3 receptor antagonist (2-APB). These results provide the first evidence that dopamine activates a receptor in adult mammalian retinal neurons that is distinct from classical D1 and D2 receptors, and that dopamine can activate mechanisms in addition to cAMP and cAMP-dependent protein kinase to modulate retinal ganglion cell excitability. J. Comp. Neurol. 520:4032-4049, 2012. © 2012 Wiley Periodicals, Inc.
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- "Blocking D 1 Rs in the absence of GABA A and glycine receptors significantly increased rather than decreased the amplitude of the dark-adapted b-wave and increased sensitivity at the brightest backgrounds tested, indicating that D 1 Rs suppress GABA C input to DBCs. D 1 R suppression of Na V channels that control GABA input to DBC GABA C Rs is similar to the actions of D 1 R on other retinal cell types (Ichinose & Lukasiewicz, 2007; Hayashida et al., 2009; Ogata et al., 2012), which act as gain controls in cone ON bipolar cells (Ichinose & Lukasiewicz, 2007) during light adaptation (Vaquero et al., 2001). "
ABSTRACT: Reducing signal gain in the highly sensitive rod pathway prevents saturation as background light levels increase, allowing the dark-adapted retina to encode stimuli over a range of background luminances. Dopamine release is increased during light adaptation and is generally accepted to suppress rod signaling in light-adapted retinas. However, recent research has suggested that dopamine, acting through D1 receptors, could additionally produce a sensitization of the rod pathway in dim light conditions via GABAc receptors. Here, we evaluate the overall activity of the depolarizing bipolar cell population (DBCs) in vivo to ensure the integrity of long-distance network interactions by quantifying the b-wave of the electroretinogram. We show that dopamine, acting through D1 receptors, reduces the amplitude and sensitivity of rod-driven DBCs during light adaptation by suppressing GABAA R-mediated serial inhibition onto rod DBC GABAC Rs. Block of D1 receptors does not suppress rod-driven DBC sensitivity when GABAA -mediated serial inhibition is blocked by gabazine, suggesting that the reduction in rod-driven DBC sensitivity in the absence of D1 receptors is due to disinhibition of serial inhibitory GABAergic circuitry rather than a direct facilitatory effect on GABA release onto rod-driven DBC GABAC receptors. Finally, the large population of GABAergic A17 wide-field amacrine cells known to maintain reciprocal inhibition with rod DBCs could be excluded from the proposed disinhibitory circuit after treatment with 5,7- dihydroxytryptamine. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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- "Neither of these proteins has been shown to directly regulate expression of the dopamine transporter or dopamine receptor genes in humans. However , both proteins are part of the bHLH transcriptional network that drives retina development (Feng et al. 2006; Pennesi et al. 2006; Skowronska-Krawczyk et al. 2004), and the dopamine receptors are critical for normal retinal function (He et al. 2013; Nguyen-Legros et al. 1999; Ogata et al. 2012; Reis et al. 2007; Yang et al. 2013). Our own transgenic expression data show strong expression of hlh-17 in the cephalic sheath cells of wild-type animals and, on its own, do not support the direct regulation of dat-1 and dop-3 by HLH-17. "
ABSTRACT: In Caenorhabditis elegans, the dopamine transporter DAT-1 regulates synaptic dopamine (DA) signaling by controlling extracellular DA levels. In dat-1(ok157) animals, DA is not taken back up presynaptically but instead reaches extrasynpatic sites where it activates the dopamine receptor DOP-3 on choligeneric motor neurons and causes animals to become paralyzed in water. This phenotype is called swimming induced paralysis (SWIP) and is dependent on dat-1 and dop-3. Upstream regulators of dat-1 and dop-3 have yet to be described in C. elegans. In our previous studies, we defined a role for HLH-17 during dopamine response through its regulation of the dopamine receptors. Here we continue our characterization of the effects of HLH-17 on dopamine signaling. Our results suggest that HLH-17 acts downstream of dopamine synthesis to regulate the expression of dop-3 and dat-1. First, we show that hlh-17 animals display a SWIP phenotype that is consistent with its regulation of dop-3 and dat-1. Second, we show that this behavior is enhanced by treatment with the dopamine reuptake inhibitor, bupropion, in both hlh-17 and dat-1 animals, a result suggesting that SWIP behavior is regulated via a mechanism that is both dependent and independent of DAT-1. Third, and finally, we show that although the SWIP phenotype of hlh-17 animals is unresponsive to the dopamine agonist, reserpine, and to the antidepressant, fluoxetine, hlh-17 animals are not defective in acetylcholine signaling. Taken together, our work suggests that HLH-17 is required to maintain normal levels of dopamine in the synaptic cleft through its regulation of dop-3 and dat-1.
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ABSTRACT: Oxidative stress is widely implicated in the death of retinal ganglion cells associated with various optic neuropathies. Agonists of the dopamine D(1) receptor have recently been found to be potentially neuroprotective against oxidative stress-induced injury. The goal of this study was to investigate whether SKF83959, a next-generation high-affinity D(1) receptor agonist, could protect retinal ganglion cell 5 (RGC-5) cells from H(2)O(2)-induced damage and the molecular mechanism involved. We examined expression of the D(1) receptor in RGC-5 cells with reverse-transcription-PCR and immunoblotting and assessed neuroprotection using propidium iodide staining and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, we monitored the activation and involvement of members of mitogen-activated protein kinase family, extracellular signal-regulated kinase (ERK), p38 and c-Jun NH(2)-terminal kinase, with western blot and specific inhibitors. We found that the D(1) receptor was expressed in RGC-5 cells, but the sequence analysis suggested this cell line is from mouse and not rat origin. SKF83959 exhibited a remarkable neuroprotective effect on H(2)O(2)-damaged RGC-5 cells, which was blocked by the specific D(1) receptor antagonist, SCH23390. ERK and p38 were activated by SKF83959, and pretreatment with their inhibitors U0126 and SB203580, respectively, significantly blunted the SKF83959-induced cytoprotection. However, the specific c-Jun NH(2)-terminal kinase inhibitor, SP600125, had no effect on the SKF83959-induced protection. We conclude that SKF83959 attenuates hydrogen peroxide-induced injury in RGC-5 cells via a mechanism involving activation of the ERK and p38 pathways and the D(1) receptor is a potential molecular target for developing neuroprotective drugs.
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