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Introduction
Monocarboxylates (MCs), such as lactate and ketone bodies, play an essential role in energy metabolism. They are not only waste metabolites of glucose or fatty acid but also substrates for energy supply in the kidney [1,2,3]. To prevent loss of such important substrates, most of the MCs are reabsorbed in the renal proximal tubule after being freely filtered through glomeruli. However, MCs that are hydrophilic in an anionic form in plasma and urine cannot pass through lipid bilayers. Sodium-coupled monocarboxylate transporters (SMCTs) have been identified as transporters that mediate the first step in the reabsorption of MCs on the apical side [4]. There are two isoforms of SMCTs, SMCT1 (SLC5A8), a high-affinity and low-capacity transporter in the S3 region of the proximal tubule [5, 6], and SMCT2 (SLC5A12), a low-affinity and high-capacity transporter in the S1 and S2 regions of the proximal tubule [7]. Despite the physiological importance of SMCTs, there is little information on the regulatory mechanism of SMCTs except for several reports about gene silencing of SMCT1 in various tumors [8,9,10] and inhibitory effects of insulin and SGK1 on SMCT1 [11].
In recent years, many PDZ (PSD-95, DglA, and ZO-1) proteins have been identified. A PDZ protein that has more than one PDZ domain is known to bind to a specific three-amino-acid sequence on a carboxylate terminus of its binding partner, a PDZ motif [11]. Three types of PDZ motifs have so far been identified: Class I domain Ser/Thr–X–Φ, Class II domain Φ–X–Φ, and Class III domain Asp/Glu–X–Φ (X = any residue and Φ = hydrophobic residue) [12, 13]. PDZ proteins are known to regulate localization of binding partners or molecular signaling by an interaction with their binding partners through their PDZ motifs. PDZK1, which was identified in sequence analysis of renal hypouricemia patients [14], interacts with the PDZ motif of the urate/anion exchanger URAT1 (Thr–Gln–Phe) and increases urate uptake via URAT1 [15]. In addition to PDZK1, the sodium/hydrogen exchange regulatory factor (NHERF) family is known as a family of PDZ proteins in the kidney [16].
SMCT1 has seven transmembrane domains (with an extracellular amino terminus and an intracellular carboxyl terminus), and the C-terminus last tripeptide (Thr–Arg–Leu) corresponds to the Class I PDZ motif. Based on these structural...