Abstract
Albinism is a genetic defect characterized by a loss of pigmentation. The neurosensory retina, which is not pigmented, exhibits pathologic changes secondary to the loss of pigmentation in the retina pigment epithelium (RPE). How the loss of pigmentation in the RPE causes developmental defects in the adjacent neurosensory retina has not been determined, but offers a unique opportunity to investigate the interactions between these two important tissues. One of the genes that causes albinism encodes for an orphan GPCR (OA1) expressed only in pigmented cells, including the RPE. We investigated the function and signaling of OA1 in RPE and transfected cell lines. Our results indicate that OA1 is a selective L-DOPA receptor, with no measurable second messenger activity from two closely related compounds, tyrosine and dopamine. Radiolabeled ligand binding confirmed that OA1 exhibited a single, saturable binding site for L-DOPA. Dopamine competed with L-DOPA for the single OA1 binding site, suggesting it could function as an OA1 antagonist. OA1 response to L-DOPA was defined by several common measures of G-protein coupled receptor (GPCR) activation, including influx of intracellular calcium and recruitment of β-arrestin. Further, inhibition of tyrosinase, the enzyme that makes L-DOPA, resulted in decreased PEDF secretion by RPE. Further, stimulation of OA1 in RPE with L-DOPA resulted in increased PEDF secretion. Taken together, our results illustrate an autocrine loop between OA1 and tyrosinase linked through L-DOPA, and this loop includes the secretion of at least one very potent retinal neurotrophic factor. OA1 is a selective L-DOPA receptor whose downstream effects govern spatial patterning of the developing retina. Our results suggest that the retinal consequences of albinism caused by changes in melanin synthetic machinery may be treated by L-DOPA supplementation.
Highlights
Albinism is a group of inherited genetic diseases in which there is a variable loss of pigmentation in the eye, hair, or skin
None of the pigmentation genes are expressed by the sensory retinal cells affected by albinism but by neighboring, retinal pigment epithelial cells (RPE)
Loss of pigmentation in RPE somehow leads to imprecise retinal development. To investigate this cellular relationship, we studied OA1, which is encoded by a gene in which mutations cause ocular albinism
Summary
Albinism is a group of inherited genetic diseases in which there is a variable loss of pigmentation in the eye, hair, or skin. There are two broad classes of albinism, ocularcutaneous albinism (OCA) and ocular albinism (OA). OCA occurs when all pigmented tissues exhibit hypopigmentation and involves genetic mutations that result in defects in the melanin synthetic machinery [3,7,8,9]. OA occurs when cutaneous tissues pigment normally, but the ocular tissues are hypopigmented [10,11]. Since the same proteins produce pigment in all tissues, OA most likely results from lack of expression of the melanogenic enzymes in ocular tissue rather than an inability to synthesize melanin, because the other tissues pigment normally
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