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(Investigative Ophthalmology and Visual Science. 2002;43:2450-2461.)
© 2002 by The Association for Research in Vision and Ophthalmology, Inc.

Lysophosphatidic Acid Receptor Signaling in Mammalian Retinal Pigment Epithelial Cells

Wallace B. Thoreson1,2, Jennifer S. Ryan3, Chanjuan Shi3, Melanie E. Kelly3,4, Eric J. Bryson1, Myron L. Toews2, Tracy L. Ediger2 and David M. Chacko1

1 From the Departments of Ophthalmology and 2 Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska; and 3 the Departments of Pharmacology and 4 Ophthalmology, Dalhousie University, Halifax, Nova Scotia, Canada.

PURPOSE. Lysophosphatidic acid (LPA) is a phospholipid growth factor that stimulates proliferation, chemotaxis, cation currents, and K+ currents in retinal pigment epithelial (RPE) cells. LPA receptor transduction was analyzed in human and rat RPE cells.

METHODS. Cells were cultured with standard methods, and signaling pathways were analyzed with a variety of approaches, including whole-cell recording, calcium imaging, and second-messenger assays.

RESULTS. LPA-activated nonselective cation currents in rat RPE were blocked by the protein tyrosine kinase (PTK) inhibitor genistein, by the MAP kinase kinase (MEK) inhibitor PD98059, and by loading cells with antibodies to G{alpha}i/o/t/z. LPA activated the MAP kinase and extracellular signal-related kinase (ERK)-1, and produced a dose-dependent inhibition of cAMP production. LPA stimulated a dose-dependent increase in [Ca2+]i that persisted in Ca2+-free medium and was reduced by pretreatment with thapsigargin, suggesting it involves release from intracellular stores. The [Ca2+]i increase was not blocked by ryanodine or the phospholipase C inhibitor U73122. LPA did not stimulate inositol phosphate production. Similar to the cation current, LPA-evoked [Ca2+]i increases were blocked by PD98059 and by loading cells with antibodies to G{alpha}i/o/t/z. RT-PCR experiments showed the presence of RNA for three LPA receptor subtypes (Edg2, -4, and -7); RNase protection assays showed the strongest expression for Edg2 receptor RNA.

CONCLUSIONS. LPA receptors in RPE cells activate pertussis toxin (PTx)-sensitive G proteins that inhibit cAMP accumulation; stimulate MAP kinase which activates a cation current and probably contributes to mitogenesis; and stimulate release of Ca2+ from intracellular stores that appears independent of IP3 and ryanodine receptor activation.






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Copyright © 2002 by the Association for Research in Vision and Ophthalmology