L-DOPA is an endogenous ligand for OA1.
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 beta-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.
Lopez
Vanessa M
VM
Department of Ophthalmology and Vision Science, The University of Arizona, Tucson, Arizona, USA.
Decatur
Christina L
CL
Stamer
W Daniel
WD
Lynch
Ronald M
RM
McKay
Brian S
BS
D000417:Albinism / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000378:metabolism*; D005136:Eye Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007980:Levodopa / Q000378:metabolism*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D002118:Calcium; D004298:Dopamine; D015259:Dopamine Agents; D005136:Eye Proteins; D007980:Levodopa; D008024:Ligands; D008562:Membrane Glycoproteins; D014442:Monophenol Monooxygenase; D009414:Nerve Growth Factors; D011480:Protease Inhibitors; D011954:Receptors, Dopamine; D015843:Serpins; D014443:Tyrosine; D000099174:Pigment Epithelium-Derived Factor; C095276:GPR143 protein, human