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OATs not only share high sequence homology, but they share many structural characteristics as well, including a sequence length of 500–600 amino acids, 12 transmembrane domains (TMDs) (composed of two 6 transmembrane domains connected by a long intracellular loop), and cytosolic N and C termini (Fig. 4.1) [13, 52]. Many structure–function analyses have been performed for various OATs, though no crystal structures are available. There are two large interconnecting loops, one between TMD 1/2 and another between TMD 6/7. The first large extracellular loop contains multiple consensus N‐glycosylation sites, as well as conserved cysteine residues [32]. The large intracellular loop, along with the intracellular carboxy terminus, contains several potential phosphorylation sites for protein kinase C (PKC), protein kinase A (PKA) [53], casein kinase II, and tyrosine kinase [13, 32]. The functional importance of kinases in the regulation of OAT function is described later in this chapter.

FIGURE 4.1 Schematic illustrating the transmembrane topology of organic anion transporters. Hydropathy analyses indicate that the OATs comprise twelve TMDs (numbered in the figure). The large loops between TMD 1 and 2 (extracellular) and TMD 6 and 7 (intracellular) contain several consensus glycosylation (G) and PKC phosphorylation (P) sites, respectively. Amino acid residues that are critical for OAT function are H (histidine), Y (tyrosine), F (phenylalanine), W (tryptophan), K (lysine), and R (arginine).

With permission from Ref. 49.