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Glutamate accelerates RPE cell proliferation through ERK1/2 activation via distinct receptor-specific mechanisms.
J Cell Biochem. 2008 May 15; 104(2):377-90.JC

Abstract

The proliferation and migration of Retinal Pigment Epithelium cells resulting from an epithelial-mesenchymal transition plays a key role in proliferative vitreoretinopathy, which leads to retinal detachment and the loss of vision. In neurons, glutamate has been shown to activate the Ras/Raf/MEK/ERK cascade, which participates in the regulation of proliferation, differentiation, and survival processes. Although glutamate-stimulation and the activation of ERK1/2 by different stimuli have been shown to promote RPE cell proliferation, the signaling pathway(s) linking these effects has not been established. We analyzed the molecular mechanisms leading to glutamate-induced proliferation by determining ERK1/2 and CREB phoshporylation in chick RPE cells in primary culture and the human-derived RPE cell line ARPE-19. This study shows for the first time, that glutamate promotes RPE cell proliferation by activating two distinct signaling pathways linked to selective glutamate receptor subtypes. Results demonstrate that glutamate stimulates RPE cell proliferation as well as ERK and CREB phosphorylation. These effects were mimicked by the mGluR agonist ACPD and by NMDA, and were prevented by the respective receptor inhibitors MCPG and MK-801, indicating a cause-effect relationship between these processes. Whereas mGluR promoted proliferation by activating the MEK/ERK/CREB cascade, NMDA stimulated proliferation through the MEK-independent activation of Ca(2+)/calmodulin-dependent kinases. The blockage of both signaling pathways to proliferation by KN-62 suggests the involvement of CaMKs in the control of glutamate-induced proliferation at a common step, downstream of CREB, possibly the regulation of cell cycle progression. Based on these findings, the participation of glutamate in the development of PVR can be considered.

Authors+Show Affiliations

Instituto de Fisiología Celular, Departamento de Neurociencias, Universidad Nacional Autónoma de México, Mexico, Mexico.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18022816

Citation

García, Sofía, et al. "Glutamate Accelerates RPE Cell Proliferation Through ERK1/2 Activation Via Distinct Receptor-specific Mechanisms." Journal of Cellular Biochemistry, vol. 104, no. 2, 2008, pp. 377-90.
García S, López E, López-Colomé AM. Glutamate accelerates RPE cell proliferation through ERK1/2 activation via distinct receptor-specific mechanisms. J Cell Biochem. 2008;104(2):377-90.
García, S., López, E., & López-Colomé, A. M. (2008). Glutamate accelerates RPE cell proliferation through ERK1/2 activation via distinct receptor-specific mechanisms. Journal of Cellular Biochemistry, 104(2), 377-90.
García S, López E, López-Colomé AM. Glutamate Accelerates RPE Cell Proliferation Through ERK1/2 Activation Via Distinct Receptor-specific Mechanisms. J Cell Biochem. 2008 May 15;104(2):377-90. PubMed PMID: 18022816.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glutamate accelerates RPE cell proliferation through ERK1/2 activation via distinct receptor-specific mechanisms. AU - García,Sofía, AU - López,Edith, AU - López-Colomé,Ana María, PY - 2007/11/21/pubmed PY - 2008/7/9/medline PY - 2007/11/21/entrez SP - 377 EP - 90 JF - Journal of cellular biochemistry JO - J. Cell. Biochem. VL - 104 IS - 2 N2 - The proliferation and migration of Retinal Pigment Epithelium cells resulting from an epithelial-mesenchymal transition plays a key role in proliferative vitreoretinopathy, which leads to retinal detachment and the loss of vision. In neurons, glutamate has been shown to activate the Ras/Raf/MEK/ERK cascade, which participates in the regulation of proliferation, differentiation, and survival processes. Although glutamate-stimulation and the activation of ERK1/2 by different stimuli have been shown to promote RPE cell proliferation, the signaling pathway(s) linking these effects has not been established. We analyzed the molecular mechanisms leading to glutamate-induced proliferation by determining ERK1/2 and CREB phoshporylation in chick RPE cells in primary culture and the human-derived RPE cell line ARPE-19. This study shows for the first time, that glutamate promotes RPE cell proliferation by activating two distinct signaling pathways linked to selective glutamate receptor subtypes. Results demonstrate that glutamate stimulates RPE cell proliferation as well as ERK and CREB phosphorylation. These effects were mimicked by the mGluR agonist ACPD and by NMDA, and were prevented by the respective receptor inhibitors MCPG and MK-801, indicating a cause-effect relationship between these processes. Whereas mGluR promoted proliferation by activating the MEK/ERK/CREB cascade, NMDA stimulated proliferation through the MEK-independent activation of Ca(2+)/calmodulin-dependent kinases. The blockage of both signaling pathways to proliferation by KN-62 suggests the involvement of CaMKs in the control of glutamate-induced proliferation at a common step, downstream of CREB, possibly the regulation of cell cycle progression. Based on these findings, the participation of glutamate in the development of PVR can be considered. SN - 1097-4644 UR - https://www.unboundmedicine.com/medline/citation/18022816/Glutamate_accelerates_RPE_cell_proliferation_through_ERK1/2_activation_via_distinct_receptor_specific_mechanisms_ L2 - https://doi.org/10.1002/jcb.21633 DB - PRIME DP - Unbound Medicine ER -