Sodium-coupled monocarboxylate transporters in normal tissues and in cancer

Abstract

SLC5A8 and SLC5A12 are sodium-coupled monocarboxylate transporters (SMCTs), the former being a high-affinity type and the latter a low-affinity type. Both transport a variety of monocarboxylates in a Na(+)-coupled manner. They are expressed in the gastrointestinal tract, kidney, thyroid, brain, and retina. SLC5A8 is localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. In the brain and retina, its expression is restricted to neurons and the retinal pigment epithelium. The physiologic functions of SLC5A8 include absorption of short-chain fatty acids in the colon and small intestine, reabsorption of lactate and pyruvate in the kidney, and cellular uptake of lactate and ketone bodies in neurons. It also transports the B-complex vitamin nicotinate. SLC5A12 is also localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. In the brain and retina, its expression is restricted to astrocytes and Müller cells. SLC5A8 also functions as a tumor suppressor; its expression is silenced in tumors of colon, thyroid, stomach, kidney, and brain. The tumor-suppressive function is related to its ability to mediate concentrative uptake of butyrate, propionate, and pyruvate, all of which are inhibitors of histone deacetylases. SLC5A8 can also transport a variety of pharmacologically relevant monocarboxylates, including salicylates, benzoate, and gamma-hydroxybutyrate. Non-steroidal anti-inflammatory drugs such as ibuprofen, ketoprofen, and fenoprofen, also interact with SLC5A8. These drugs are not transportable substrates for SLC5A8, but instead function as blockers of the transporter. Relatively less is known on the role of SLC5A12 in drug transport.

Fig. 1

Transport of γ-Hydroxybutyrate Via Human SLC5A8 in a Mammalian Cell Expression System. Human SLC5A8 Was Expressed Heterologously in Human Retinal Pigment Epithelial Cell Lines HRPE by cDNA Transfection. Cells Transfected with pSPORT1 Vector Served as the Control. a Uptake of [³H]-γ-Hydroxybutyrate (25 nM) Was Measured in These Cells for 15 min in the Presence (NaCl Buffer) or Absence (N-methyl-d-glucamine Chloride Buffer) of Na⁺. b Uptake of [³H]-γ-Hydroxybutyrate (25 nM) Was Measured in a NaCl Buffer in Vector-transfected Cells and SLC5A8 cDNA-transfected Cells in the Presence or Absence of Unlabeled Monocarboxylate Substrates (5 mM) of the Transporter

Fig. 2

Transport of γ-Hydroxybutyrate Via Human SLC5A8 in the X. laevis Oocyte Expression System. Human SLC5A8 Was Expressed Heterologously in X. laevis Oocytes by cRNA Injection. Water-injected Oocytes Served as the Control. Transport of γ-Hydroxybutryate via SLC5A8 was Monitored Electrophysiologically using the Two-microelectrode Voltage-clamp Technique, with Membrane Potential Clamped at −50 mV. γ-Hydroxybutyrate (GHB) Induced Inward Currents in SLC5A8-expressing Oocytes. In Contrast, There Were No Currents in Water-injected Oocytes Under Similar Conditions. a Saturation Kinetics of GHB-induced Currents. b Na⁺-activation Kinetics of GHB-induced Currents. Since the Expression Levels Varied from Oocyte to Oocyte, the Maximal Current Induced in Each Oocyte Was Taken as 1, and the Currents Induced in the Same Oocyte at Different Experimental Conditions Were Expressed as a Fraction of this Maximal Current. The Michaelis Constant Was Calculated by Fitting the Experimental Data from Saturation Kinetics to Michaelis–Menten Equation Describing a Single Saturable System. The Hill Coefficient Was Calculated by Fitting the Experimental Data from Na⁺-activation Kinetics to Hill Equation