A guide to plasma membrane solute carrier proteins

Abstract

This review aims to serve as an introduction to the solute carrier proteins (SLC) superfamily of transporter proteins and their roles in human cells. The SLC superfamily currently includes 458 transport proteins in 65 families that carry a wide variety of substances across cellular membranes. While members of this superfamily are found throughout cellular organelles, this review focuses on transporters expressed at the plasma membrane. At the cell surface, SLC proteins may be viewed as gatekeepers of the cellular milieu, dynamically responding to different metabolic states. With altered metabolism being one of the hallmarks of cancer, we also briefly review the roles that surface SLC proteins play in the development and progression of cancer through their influence on regulating metabolism and environmental conditions.

Structural Similarities between Some Common Fluorophores Used in Biology, Marketed Drugs, Endogenous Metabolites, and Natural Products

“…However, given that most of these probes are contemporary, synthetic molecules, the uptake transporters for which they are substrates are nonetheless often ancient [ 43 , 44 ], and must have evolved in nature for other purposes. These purposes may reasonably be expected to include the uptake of endogenous metabolites in multicellular organisms [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ], as well as exogenous natural products whose uptake can enhance biological fitness (e.g., [ 54 , 55 ]). This explanation does seems to hold well for synthetic, marketed pharmaceutical drugs [ 55 ].…”

Membrane Transport Proteins in Osteoclasts: The Ins and Outs

“…Some of these transporters are ubiquitously expressed while others are a specialized feature of terminally differentiated cell types like neurons and OCs. All members of this superfamily have a preferred substrate and subcellular localization allowing for a vast number of varied exchanges across biological membranes intracellularly and with the extracellular environment (Pizzagalli et al, 2020). A number of diverse SLC transporters have been recently linked to OC function involved in the exchange of a range of fundamental biological substrates including amino acids (SLC7A5/LAT1, SLC9B, SLC17A7/VGLUT1), nucleosides (SLC29A3) and iron (SLC40A1 and SLC11A2) that are described briefly herein.…”

“…Despite its abundance in OCs, Slc9b2 knockout mice lack a prominent skeletal phenotype (Hofstetter et al, 2010). Further, OCs from Slc9b2 deficient mice differentiate normally and are capable of bone resorption in vitro, suggesting that SLC9B2 is dispensable in OCs or may be compensated by a hitherto unidentified transporter that fulfills its function (Pizzagalli et al, 2020).…”

“…In fact, outside of G-protein coupled receptors (GPCRs), the most intensively studied drug targets, membrane transport proteins constitute the largest but most understudied group of potential new drug targets (Schumann et al, 2020). For example, more than 30 transporters of the SLC superfamily have recently been presented as current, prospective, or potential drug targets (Lin et al, 2015b;Schumann et al, 2020;Wang et al, 2020) and spawned strategic partnerships between pharmaceutical industry and academia, the largest conglomerate called RESOLUTE (Research Empowerment on Solute Carriers) (Pizzagalli et al, 2020). In addition, multiple drug classes targeting membrane transporters have already reached the market, with several additional drugs in phase II clinical trials, many aimed at targeting metabolic diseases (Lin et al, 2015b;Zhang Y. et al, 2018;Schumann et al, 2020).…”

“…In their simplest form, membrane transport proteins are considered 'gatekeepers' of molecular exchanges across biological membranes and are operationally categorized according to their mode, direction and molecule of transport: i.e., (i) channels, (ii) gated channels, (iii) primary active transporters and (iv) secondary active transporters (uniporters, symporters and antiporters, inclusive) (Figure 2A). These integral transmembrane proteins can be further subdivided into four main superfamilies: (i) the ATP-binding cassette (ABC) transporters, (ii) ATPases, (iii) ion channels, and (iv) solute carrier proteins (SLCs) (reviewed extensively in (Pizzagalli et al, 2020)).…”