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A. A. Deora, Z. Jiang, E. Rodriguez-Boulan, N. Philp; Monocarboxylate Transporter (MCT) and CD147 Interacting Domains Necessary for Functional Heterodimeric MCT Complex. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3064.
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© ARVO (1962-2015); The Authors (2016-present)
The retina is metabolically very active and visual function is maintained by energy produced by glycolysis and oxidative phosphorylation. Lactate produced as an end product of gylcolysis in Muller cells fuels oxidative phosphorylation by photoreceptor cells. Transport of lactate in the retina is facilitated by a family of proton-coupled MCTs. MCT1 and MCT4 are expressed throughout the neural retina and MCT1 and MCT3 are expressed in the apical and basolateral membrane of the RPE, respectively. MCT4 is expressed in the RPE at early stages of eye development but, in the adult eye, RPE expresses MCT3.The functional transporter is a heteromers comprised of a multi-spanning membrane protein, MCT linked to CD147, a single-span type I glycoprotein. CD147 null mice do not express MCT1, MCT3 and MCT4 protein. An important role for heterodimeric MCT complex in retina is underscored by the finding that these mice are blind as shown by abnormal ERG. The purpose of these studies was to identify domains of CD147 and MCT necessary for maturation of the functional heteromeric MCT/CD147 complex.
C-terminal truncations and site-specific mutations were made in CD147 and MCTs cDNAs. Wild type and mutant constructs were transfected into polarized ARPE-19 cells and Madin-Darby canine kidney cells grown on Transwell filters and cells were used for biochemical and immunofluoroscence analyses.
The C-terminal domain truncated CD147 does not interact with MCT1, 3, 4, and prevents their cell surface expression. Deletion of the acidic cluster (DEDD) in the cytoplasmic domain of CD147 altered MCT4 but not MCT1 trafficking to the cell surface. When co-expressed, MCT3 and 4 negatively regulate each other’s expression suggesting, they may interact with the same domain of CD147. C-terminal truncations of MCT1, 3 and 4 also resulted in abrogation of formation of the MCT/CD147 complex.
Formation of the mature MCT complex at the cell-surface requires interaction between the cytoplasmic domains of both MCTs and CD147. Our results demonstrate that distinct sites on C-terminal of CD147 regulate its interaction with different MCT isoforms and may be crucial for co-expression of multiple MCT family members in the same cell. Our finding also helps explain the isoform switching of MCT4 and MCT3 that occurs in RPE during development. Thus, our results provide important insights on the molecular and the cellular mechanisms underlying lactate homeostasis in the retina.
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