Daniele Lauren L, Sauer Brian, Gallagher Shannon M, Pugh Edward N, Philp Nancy J
F.M. Kirby Center for Molecular Ophthalmology, Department of Ophthalmology, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Am J Physiol Cell Physiol. 2008 Aug;295(2):C451-7. doi: 10.1152/ajpcell.00124.2008. Epub 2008 Jun 4.
To meet the high-energy demands of photoreceptor cells, the outer retina metabolizes glucose through glycolytic and oxidative pathways, resulting in large-scale production of lactate and CO(2). Mct3, a proton-coupled monocarboxylate transporter, is critically positioned to facilitate transport of lactate and H(+) out of the retina and could therefore play a role in pH and ion homeostasis of the outer retina. Mct3 is preferentially expressed in the basolateral membrane of the retinal pigment epithelium and forms a heteromeric complex with the accessory protein CD147. To examine the physiological role of Mct3 in the retina, we generated mice with a targeted deletion in Mct3 (slc16A8). The overall retinal histology of 4- to 36-wk-old Mct3(-/-) mice appeared normal. In the absence of Mct3, expression of CD147 was lost from the basolateral but not apical RPE. The saturated a-wave amplitude (a(max)) of the scotopic electroretinogram (ERG) was reduced by approximately twofold in Mct3(-/-) mice relative to wild-type mice. A fourfold increase in lactate in the retina suggested a decrease in outer-retinal pH. In single-cell recordings from superfused retinal slices, saturating amplitudes of single rod photocurrents (J(max)) were comparable indicating that Mct3(-/-) mouse photoreceptor cells were inherently healthy. Based on these data, we hypothesize that disruption of Mct3 leads to a potentially reversible decrease in subretinal space pH, thereby reducing the magnitude of the light suppressible photoreceptor current.
为了满足光感受器细胞对高能的需求，视网膜外层通过糖酵解和氧化途径代谢葡萄糖，从而大规模产生乳酸和二氧化碳。Mct3是一种质子偶联单羧酸转运体，在促进乳酸和氢离子从视网膜输出方面起着关键作用，因此可能在外层视网膜的pH值和离子稳态中发挥作用。Mct3优先表达于视网膜色素上皮的基底外侧膜，并与辅助蛋白CD147形成异聚复合物。为了研究Mct3在视网膜中的生理作用，我们构建了Mct3（slc16A8）靶向缺失的小鼠。4至36周龄的Mct3基因敲除小鼠的整体视网膜组织学看起来正常。在缺乏Mct3的情况下，基底外侧而非顶端视网膜色素上皮细胞中CD147的表达缺失。与野生型小鼠相比，Mct3基因敲除小鼠暗视视网膜电图（ERG）的饱和a波振幅（a(max)）降低了约两倍。视网膜中乳酸增加四倍表明外层视网膜pH值降低。在对灌注视网膜切片的单细胞记录中，单根视杆光电流的饱和振幅（J(max)）相当，表明Mct3基因敲除小鼠的光感受器细胞本身是健康的。基于这些数据，我们推测Mct3的破坏会导致视网膜下间隙pH值潜在的可逆性降低，从而降低光可抑制的光感受器电流的幅度。
