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L-DOPA is an endogenous ligand for OA1.

Publication ,  Journal Article
Lopez, VM; Decatur, CL; Stamer, WD; Lynch, RM; McKay, BS
Published in: PLoS Biol
September 30, 2008

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.

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Published In

PLoS Biol

DOI

EISSN

1545-7885

Publication Date

September 30, 2008

Volume

6

Issue

9

Start / End Page

e236

Location

United States

Related Subject Headings

  • Tyrosine
  • Signal Transduction
  • Serpins
  • Receptors, Dopamine
  • Protease Inhibitors
  • Pigment Epithelium of Eye
  • Nerve Growth Factors
  • Monophenol Monooxygenase
  • Membrane Glycoproteins
  • Ligands
 

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Lopez, V. M., Decatur, C. L., Stamer, W. D., Lynch, R. M., & McKay, B. S. (2008). L-DOPA is an endogenous ligand for OA1. PLoS Biol, 6(9), e236. https://doi.org/10.1371/journal.pbio.0060236
Lopez, Vanessa M., Christina L. Decatur, W Daniel Stamer, Ronald M. Lynch, and Brian S. McKay. “L-DOPA is an endogenous ligand for OA1.PLoS Biol 6, no. 9 (September 30, 2008): e236. https://doi.org/10.1371/journal.pbio.0060236.
Lopez VM, Decatur CL, Stamer WD, Lynch RM, McKay BS. L-DOPA is an endogenous ligand for OA1. PLoS Biol. 2008 Sep 30;6(9):e236.
Lopez, Vanessa M., et al. “L-DOPA is an endogenous ligand for OA1.PLoS Biol, vol. 6, no. 9, Sept. 2008, p. e236. Pubmed, doi:10.1371/journal.pbio.0060236.
Lopez VM, Decatur CL, Stamer WD, Lynch RM, McKay BS. L-DOPA is an endogenous ligand for OA1. PLoS Biol. 2008 Sep 30;6(9):e236.
Journal cover image

Published In

PLoS Biol

DOI

EISSN

1545-7885

Publication Date

September 30, 2008

Volume

6

Issue

9

Start / End Page

e236

Location

United States

Related Subject Headings

  • Tyrosine
  • Signal Transduction
  • Serpins
  • Receptors, Dopamine
  • Protease Inhibitors
  • Pigment Epithelium of Eye
  • Nerve Growth Factors
  • Monophenol Monooxygenase
  • Membrane Glycoproteins
  • Ligands