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Endogenous Gas6 and Ca2+ -channel activation modulate phagocytosis by retinal pigment epithelium.
- Source :
-
Cellular signalling [Cell Signal] 2008 Jun; Vol. 20 (6), pp. 1159-68. Date of Electronic Publication: 2008 Feb 16. - Publication Year :
- 2008
-
Abstract
- Mutation or loss of MerTK as well as deficiency of alphavbeta5-integrins, gives rise to retinal-degeneration due to inefficient phagocytosis of photoreceptor outer-segment fragments by the retinal pigment epithelium (RPE). This study shows that Gas6 expressed endogenously by human RPE promotes phagocytosis. The RPE expresses Gas6 more highly in vivo and in serum-reduced conditions in vitro than in high-serum conditions, suggesting a negative-feedback control. An antibody-blockage approach revealed that Gas6-expressing RPE phagocytizes photoreceptor outer-segment fragments due to stimulation of MerTK by endogenous Gas6 in vitro. MerTK- and Gas6-antibodies reduced phagocytosis. Blocking L-type Ca(2+)-channels with nifedipine inhibited MerTK dependent phagocytosis in vitro. Application of integrin inhibitory, soluble, RGD-containing peptides or soluble vitronectin reduced L-type Ca(2+)-channel currents in RPE. Herbimycin A, which reduces phosphorylation of integrin receptor-associated proteins and decreases L-type Ca(2+)-channel currents in RPE, eliminates the inhibiting vitronectin effect and abolishes phagocytosis. Thus, Gas6-promoted phagocytosis was inhibited by L-type Ca(2+)-channel blockage, which in turn may be activated by integrin receptor stimulation. These results suggest that L-type Ca(2+)-channels could be regulated downstream of both MerTK and alphavbeta5-integrin, indicating that the binding and uptake mechanisms of phagocytosis are part of a converging pathway.
- Subjects :
- Antibodies pharmacology
Benzoquinones pharmacology
Calcium Channel Blockers pharmacology
Cells, Cultured
Humans
Integrin alphaV metabolism
Intercellular Signaling Peptides and Proteins analysis
Intercellular Signaling Peptides and Proteins immunology
Lactams, Macrocyclic pharmacology
Ligands
Nifedipine pharmacology
Pigment Epithelium of Eye drug effects
Pigment Epithelium of Eye enzymology
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins antagonists & inhibitors
Proto-Oncogene Proteins immunology
Proto-Oncogene Proteins metabolism
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Receptor Protein-Tyrosine Kinases immunology
Receptor Protein-Tyrosine Kinases metabolism
Rifabutin analogs & derivatives
c-Mer Tyrosine Kinase
Calcium Channels, L-Type metabolism
Intercellular Signaling Peptides and Proteins metabolism
Phagocytosis drug effects
Pigment Epithelium of Eye metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0898-6568
- Volume :
- 20
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cellular signalling
- Publication Type :
- Academic Journal
- Accession number :
- 18395422
- Full Text :
- https://doi.org/10.1016/j.cellsig.2008.02.005