Photoreceptor Rescue By Inhibition of Dopamine Signaling

描述（由申请人提供）：由于cgmp -磷酸二酯酶基因β亚基的缺陷，rd1小鼠的杆状光感受器在体内或器官培养中在一个月大时退化。与大多数视网膜色素变性模型一样，变性的潜在机制仍然知之甚少。多巴胺是一种神经调节剂，影响脊椎动物视网膜中大多数（如果不是全部）细胞类型。我们发现来自D1或d2受体家族的多巴胺拮抗剂完全阻断rd1视网膜器官培养模型中光感受器的退化。目前关于多巴胺能功能的理论模型和观察未能解释这一令人惊讶的结果。例如，只有D4受体亚型在小鼠光感受器中被明确识别；但还是d1家族

DESCRIPTION (provided by applicant): The rod photoreceptors of the rd1 mouse degenerate in vivo or in organ culture by one month of age as a result of a defect in the beta-subunit of the cGMP-phosphodiesterase gene. As with most models of retinitis pigmentosa, the underlying mechanism of degeneration remains poorly understood. Dopamine is a neuromodulator affecting most, if not all, cell types in the vertebrate retina. We have discovered that dopamine antagonists from either the D1- or D2-receptor families completely block the degeneration of photoreceptors in the rd1 retinal organ culture model. Current theoretical models and observations of dopaminergic function fail to explain this surprising result. For example, only the D4 receptor subtype has been clearly identified in mouse photoreceptors; yet a D1-family antagonist is equally protective. Also, D1- and D2-family receptors generally act through opposing pathways to modulate the effects of the other; here they give the same result. Finally, dopamine generally has subtle, modulatory effects in the retina; here the effect on cell survival is dramatic and complete - no morphological difference can be detected between wild type and treated rdl organ cultures after 4 weeks, when nearly all of the rods have degenerated in the untreated rd1 culture. We propose experiments to address these differences and to test the significance of our findings in vivo. First, we will determine whether the absence of dopamine receptors can increase photoreceptor survival and function in the rd1 mouse retina in vivo. Secondly, we will address two aspects of the underlying mechanism, first testing a novel hypothesis concerning dopamine receptors, a subtype of the larger G-protein-coupled receptor family. In a recent paradigm shift, G-protein-coupled receptors, previously thought to function only as monomers, are now recognized to sometimes form heterodimers with atypical pharmacology and function. Such novel characteristics have recently been demonstrated with opioid, GABA, and other GPCRs. The formation of heterodimers comprised of different dopamine receptor subtypes could explain many of the perceived incongruities. We will also determine if D1-family dopamine receptors are present in rd1 photoreceptors. The proposed experiments will generate two important results. First, we will determine the importance of dopamine signaling in photoreceptor degeneration in vivo, which could lead to entirely new therapeutic approaches for retinal degeneration. Secondly, we will investigate the underlying mechanism including testing a dopamine receptor heterodimer-induced model of degeneration which could lead to a new area of investigation in retinal cell biology.