Dataset Information

Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family.

ABSTRACT:

Objective

Thyroid hormone (TH) transport represents a critical first step in governing intracellular TH regulation. It is still unknown whether the full repertoire of TH transporters has been identified. Members of the solute carrier (SLC) 22 family have substrates in common with the known TH transporters of the organic anion-transporting peptide family. Therefore, we screened the SLC22 family for TH transporters.

Methods

Uptake of 1 nM of iodothyronines or sulfated iodothyronines in COS1 cells expressing SLC22 proteins was performed.

Results

We first tested 25 mouse (m) SLC22 proteins for TH uptake and found that the majority of the organic anion transporter (OAT) clade were capable of 3,3',5-triiodothyronine and/or thyroxine (T4) transport. Based on phylogenetic tree analysis of the mouse and human (h) SLC22 family, we selected eight hSLC22s that grouped with the newly identified mouse TH transporters. Of these, four tested positive for uptake of one or more substrates, particularly hSLC22A11 showed robust (3-fold over control) uptake of T4. Uptake of sulfated iodothyronines was strongly (up to 17-fold) induced by some SLC22s, most notably SLC22A8, hSLC22A9, mSLC22A27 and mSLC22A29. Finally, the zebrafish orthologues of SLC22A6/8 drOatx and drSlc22a6l also transported almost all (sulfated) iodothyronines tested. The OAT inhibitors lesinurad and probenecid inhibited most SLC22 proteins.

Conclusions

Our results demonstrated that members of the OAT clade of the SLC22 family constitute a novel, evolutionary conserved group of transporters for (sulfated) iodothyronines. Future studies should reveal the relevance of these transporters in TH homeostasis and physiology.

SUBMITTER: Chen Z

PROVIDER: S-EPMC10305468 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family.

Chen Zhongli Z Peeters Robin P RP Flach Wesley W de Rooij Linda J LJ Yildiz Sena S Teumer Alexander A Nauck Matthias M Sterenborg Rosalie B T M RBTM Rutten Joost H W JHW Medici Marco M Edward Visser W W Meima Marcel E ME

European thyroid journal 20230615 4

<h4>Objective</h4>Thyroid hormone (TH) transport represents a critical first step in governing intracellular TH regulation. It is still unknown whether the full repertoire of TH transporters has been identified. Members of the solute carrier (SLC) 22 family have substrates in common with the known TH transporters of the organic anion-transporting peptide family. Therefore, we screened the SLC22 family for TH transporters.<h4>Methods</h4>Uptake of 1 nM of iodothyronines or sulfated iodothyronines ...[more]

PMID: 37074673

Similar Datasets

Project description:The human Solute Carrier 22 family (SLC22), also termed the organic ion transporter family, consists of 28 distinct multi-membrane spanning proteins, which phylogenetically cluster together according to their charge specificity for organic cations (OCTs), organic anions (OATs) and organic zwitterion/cations (OCTNs). Some SLC22 family members are well characterized in terms of their substrates, transport mechanisms and expression patterns, as well as their roles in human physiology and pharmacology, whereas others remain orphans with no known ligands. Pharmacologically, SLC22 family members play major roles as determinants of the absorption and disposition of many prescription drugs, and several including the renal transporters, OCT2, OAT1 and OAT3 are targets for many clinically important drug-drug interactions. In addition, mutations in some of these transporters (SLC22A5 (OCTN2) and SLC22A12 (URAT1) lead to rare monogenic disorders. Genetic polymorphisms in SLC22 transporters have been associated with common human disease, drug response and various phenotypic traits. Three members in this family were deorphaned in very recently: SLC22A14, SLC22A15 and SLC22A24, and found to transport specific compounds such as riboflavin (SLC22A14), anti-oxidant zwitterions (SLC22A15) and steroid conjugates (SLC22A24). Their physiologic and pharmacological roles need further investigation. This review aims to summarize the substrates, expression patterns and transporter mechanisms of individual SLC22 family members and their roles in human disease and drug disposition and response. Gaps in our understanding of SLC22 family members are described. Significance Statement In recent years, three members of the SLC22 family of transporters have been deorphaned and found to play important roles in the transport of diverse solutes. New research has furthered our understanding of the mechanisms, pharmacological roles, and clinical impact of SLC22 transporters. This minireview provides overview of SLC22 family members of their physiologic and pharmacologic roles, the impact of genetic variants in the SLC22 family on disease and drug response, and summary of recent studies deorphaning SLC22 family members.

Dataset Information

Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family.

Objective

Methods

Results

Conclusions

Publications

Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets