Emerging Roles of the Human Solute Carrier 22 Family

Abstract

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 STATEMENTIn 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.

Structural basis of organic cation transporter-3 inhibition

“…The SLC22 family comprises more than 30 transporters, which facilitate the transport of organic cations (OCTs), anions (OATs) and zwitterions (OCTNs) 1 . Collectively, these transporters define the pharmacokinetics of a vast array of drugs and xenobiotics 41,42 . Herein, we describe the cryo-EM structure of OCT3 and provide the first direct insights into the organization of a SLC22 member, its substrate permeation pathway and ligand binding pocket.…”

“…Moreover, as new therapeutic strategies involving OCTs emerge in a number of different areas, a better understanding of how genetic variations affect transporter function may be useful to understand personalized variations in drug response and to develop effective pharmacogenomics-based therapeutic strategies. Thus, the deeper knowledge of the structure and function of OCTs brings us closer to more precise and efficient medical treatments 22,41,42 . Therefore, our structures provide a new starting point for rational drug development targeting OCT3 in the treatment of depression 22,50 , diabetes 11,12,51 , cardiac disease 10,15 , and cancer chemotherapy 19,39,52 .…”

A Biological Basis for Pharmacokinetics: The Remote Sensing and Signaling Theory

“…These mice also had defects in the renal elimination of diuretics and other drugs. While much of the field was characterizing drugs handled by multispecific transporters of the family, other oligospecific and (relatively) monospecific SLC22 family members were discovered; many of these have now been shown to be central to metabolism and signaling 8 . For example a close relative of OAT1 in mice that is mainly expressed in the olfactory system binds odorants with much higher affinity than OAT1 9 .…”

“…While much of the field was characterizing drugs handled by multispecific transporters of the family, other oligospecific and (relatively) monospecific SLC22 family members were discovered; many of these have now been shown to be central to metabolism and signaling. 8 For example a close relative of OAT1 in mice that is mainly expressed in the olfactory system binds odorants with much higher affinity than OAT1. 9 These and other data led us to consider the endogenous functions not only of SLC22 transporters, but of all other transporters, enzymes, and regulatory protein families implicated in ADME of small molecule drugsparticularly in the context of remote organ communication.…”

High Affinity Decynium-22 Binding to Brain Membrane Homogenates and Reduced Dorsal Camouflaging after Acute Exposure to it in Zebrafish

“…In mammals, there are three isoforms: OCT1 is richly expressed in the liver, kidneys, and gut; OCT2 is widely found in the brain, kidneys, and to a lesser extent, in other peripheral organs; and OCT3 is predominant in the heart, lungs, adipose tissue, placenta, and brain, and also occurs in other peripheral organs ( Koepsell et al, 2007 ; Nies et al, 2011 ; Koepsell, 2020 ; Samodelov et al, 2020 ; Sweet, 2021 ). Substrates of mammalian OCTs include the biogenic amines serotonin, norepinephrine, dopamine, and histamine; antioxidants; vitamins such as choline and thiamine; metabolites such as guanidine or putrescine; xenobiotic compounds including drugs such as metformin; and cationic neurotoxins such as the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cation, 1-methyl-4-phenyl pyridinium (MPP+), or paraquat cations that are used to model Parkinson’s disease in rodents ( Cui et al, 2009 ; Rappold et al, 2011 ; Nies et al, 2011 ; Bönisch, 2021 ; Yee and Giacomini, 2021 ). The pseudoisocyanine 1-1′-diethyl-2,2′cyanine iodide (decynium-22 or D-22) blocks human and mouse OCTs at low nM concentrations, and because of this property, D-22 is a useful pharmacological tool in the studies of OCT functions ( Hayer et al, 1999 ; Hayer-Zillgen et al, 2002 ; Fraser-Spears et al, 2019 ; ; Bönisch, 2021 ).…”