Reclassification of SLC22 Transporters: Analysis of OAT, OCT, OCTN, and other Family Members Reveals 8 Functional Subgroups

Abstract

Among transporters, the SLC22 family is emerging as a central hub of endogenous physiology. The family consists of organic anion transporters (OATs), organic cation transporters (OCTs) and zwitterion transporters (OCTNs). Despite being known as "drug" transporters, these multi-specific, oligo-specific, and relatively mono-specific transporters facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups with four new subgroups arising from the previously defined OAT subclade. These OAT subgroups are: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Functional support for the eight subgroups comes from network analysis of data from GWAS, in vivo models, and in vitro assays. These data emphasize shared substrate specificity of SLC22 transporters for characteristic metabolites such as prostaglandins, uric acid, carnitine, creatinine, and estrone sulfate. Some important subgroup associations include: OATS1 with metabolites, signaling molecules, uremic toxins and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with monoamine neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. The OAT-like and OAT-related subgroups remain understudied and therefore do not have assigned functionality. Relatedness within subgroups is supported by multiple sequence alignments, evolutionarily conserved protein motifs, genomic localization, and tissue expression. We also highlight low level sequence similarity of SLC22 members with other non-transport proteins. Our data suggest that the SLC22 family can work among itself, as well as with other transporters and enzymes, to optimize levels of numerous metabolites and signaling molecules, as proposed by the Remote Sensing and Signaling Theory.