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L. L. Daniele, E. N. Pugh, Jr., B. Sauer, N. J. Philp; Impaired Photoreceptor Function in Mice Lacking RPE Specific Monocarboxylate Transporter (MCT3); Possible Role for MCT3 in pH Regulation of the Subretinal Space. Invest. Ophthalmol. Vis. Sci. 2007;48(13):605.
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The retina is one of the most metabolically active tissues in the body and produces large quantities of lactate both in the light and in the dark. Proton coupled monocarboxylate transporters (MCTs) expressed in the apical (MCT1) and basolateral (MCT3) membranes of the RPE regulate transport of excess lactate from the retina to the choroid leading to the hypothesis that MCTs are essential for regulating pH and osmolarity of the subretinal space (SRS). To test this hypothesis we examined photoreceptor cell function in mice with targeted deletion of the MCT3 (slc16a8) gene.
Electroretinogram (ERG) and single cell recordings were used to assess photoreceptor cell function. ERG a-wave responses were measured in age-matched Mct3-/- and wild type (wt) mice using published protocols. Following the ERG, eyes were removed and fixed for histological analysis. Suction electrode recordings were made from rods in small slices of retina of Mct3-/- and (wt) mice: the tissue was continuously perfused with bicarbonate buffered Locke’s solution, pH 7.4, 35-37 C, and photocurrent responses to brief, calibrated flashes were recorded. Rods were selected for recording solely on the basis of straight morphology; sampling was otherwise completely random.
Histologically, the retinas of Mct3-/- mice appeared normal. However, the saturated a-wave amplitude (amax) of the scotopic ERG was reduced by a factor of ~2 in Mct3-/- mice relative to wt at all ages tested (4 weeks, ~9 weeks and 9 months): for mice > 4 wks, amax = 149 ± 16 µV (Mct3-/- , n=16) and 343 ± 15 µV (wt, n=12; mean ± s.e.m.). In striking contrast, the saturating amplitudes of the rod photocurrents (Jmax ) were comparble: Jmax = 11.3 pA ± 1.6 (Mct3-/-, n=8) and 12.8 pA ± 0.8 (wt, n=10).
The unaltered Jmax of Mct3-/- rods in perfused retinal slices indicates that they are intrinsically healthy. The discrepancy between reduced amax and unaltered Jmax in Mct3-/- vs. wt can be explained by alternation(s) in the extracellar space, e.g., a decrease in the pH of the SRS. The coordinated transport activities of MCT1 and MCT3 regulate the transepithelial transport of lactic acid, H+, and H2O from the retina to the choroid. The rod circulating current is reduced by low extracellular pH1. We thus hypothesize that deletion of MCT3 impairs proton-coupled lactate transport out of the retina and lowers the pH of the SRS.Leibman, Mueller, and Pugh, Jr., J physiol. 1984
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