Reactome | SLC-mediated transmembrane transport

SLC-mediated transmembrane transport

Stable Identifier

R-HSA-425407

DOI

10.3180/REACT_19118.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Proteins with transporting functions can be roughly classified into 3 categories: ATP-powered pumps, ion channels, and transporters. Pumps utilize the energy released by ATP hydrolysis to power the movement of the substrates across the membrane, against their electrochemical gradient. Channels at the open state can transfer the substrates (ions or water) down their electrochemical gradient, at an extremely high efficiency (up to 108 s-1). Transporters facilitate the movement of a specific substrate either against or following their concentration gradient, at a lower speed (about 102 -104 s-1); as generally believed, conformational change of the transporter protein is involved in the transfer process.

According to the Human Genome Organization (HUGO) Gene Nomenclature Committee, all human transporters can be grouped into the solute-carrier (SLC) superfamily (http://www.genenames.org/genefamilies/SLC). Currently, there are 55 SLC families in the superfamily, with a total of at least 362 putatively functional protein-coding genes (Hediger et al. 2004, He et al. 2009; http://www.bioparadigms.org/slc/intro.htm). At least 20-25% amino-acid sequence identity is shared by members belonging to the same SLC family. No homology is shared between different SLC families. While the HUGO nomenclature system by definition only includes human genes, the nomenclature system has been informally extended to include rodent species through the use of lower cases letters (e.g., Slc1a1 denotes the rodent ortholog of the human SLC1A1 gene). And it's worthwhile to mention that pumps, channels and aquaporins are not included in SLC superfamily.

To date, nine SLC gene families (SLC4, SLC5, SLC8, SLC9, SLC12, SLC20, SLC24, SLC26 and SLC34) comprise the group that exclusively transports inorganic cations and anions across membranes. A further eight SLC gene families (SLC1, SLC6, SLC7, SLC16, SLC25, SLC36, SLC38 and SLC43) are involved in the transport of amino acids and oligopeptides (He et al. 2009). Two gene families are responsible for glucose transport in humans. SLC2 (encoding GLUTs) and SLC5 (encoding SGLTs) families mediate glucose absorption in the small intestine, glucose reabsorption in the kidney, glucose uptake by the brain across the blood-brain barrier and glucose release by all cells in the body (Wood & Trayhurn 2003).

SLC transporters are able to transport bile salts, organic acids, metal ions and amine compounds. Myo-Inositol is a precursor to phosphatidylinositols (PtdIns) and to the inositol phosphates (IP), which serve as second messengers and also act as key regulators of many cell functions (Schneider 2015). Mono-, di- and tri-carboxylate transporters mediate the transport of these acids across cellular membranes (Pajor 2006, Morris & Felmlee 2008). Essential metals are transported by metal-transporting proteins, which also control their efflux to avoid toxic build-up (Bressler et al. 2007). The SLC6 gene family encodes proteins that mediate neurotransmitter uptake in the central nervous system (CSN) and peripheral nervous system (PNS), thus terminating a synaptic signal (Chen et al. 2004). Urea transport is particularly important in the process of urinary concentration and for rapid urea equilibrium in non-renal tissues (Olives et al. 1994). Choline uptake is the rate-limiting step in the synthesis of the neurotransmitter acetylcholine. SLC genes SLC5A7 and the SLC44 family encode choline transporters (Traiffort et al. 2005). The SLC22 gene family of solute carriers function as organic cation transporters (OCTs), cation/zwitterion transporters (OCTNs) and organic anion transporters (OATs). They play important roles in drug absorption and excretion. Substrates include xenobiotics, drugs, and endogenous amine compounds (Koepsell & Endou 2004).

The human SLC5A6 encodes the Na+-dependent multivitamin transporter SMVT (Prasad et al. 1999). SMVT co-transports biotin (vitamin B7), D-Pantothoate (vitamin B5) and lipoic acid into cells with Na+ ions electrogenically. Four SLC gene families encode transporters that play key roles in nucleoside and nucleobase uptake for salvage pathways of nucleotide synthesis, and in the cellular uptake of nucleoside analogues used in the treatment of cancers and viral diseases (He et al. 2009). The human gene SLC33A1 encodes acetyl-CoA transporter AT1 (Kanamori et al. 1997). Acetyl-CoA is transported to the lumen of the Golgi apparatus, where it serves as the substrate of acetyltransferases that O-acetylates sialyl residues of gangliosides and glycoproteins. Nucleotide sugars are used as sugar donors by glycosyltransferases to create the sugar chains for glycoconjugates such as glycoproteins, polysaccharides and glycolipids. The human solute carrier family SLC35 encode nucleotide sugar transporters (NSTs), localised on Golgi and ER membranes, which can mediate the antiport of nucleotide sugars in exchange for the corresponding nucleoside monophosphates (eg. UMP for UDP-sugars) (Handford et al. 2006). Long chain fatty acids (LCFAs) can be used for energy sources and steroid hormone synthesis and regulate many cellular processes such as inflammation, blood pressure, the clotting process, blood lipid levels and the immune response. The SLC27A family encode fatty acid transporter proteins (FATPs) (Anderson & Stahl 2013). The SLC gene family members SLCO1 SLCO2 and SLCO3 encode organic anion transporting polypeptides (OATPs). OATPs are membrane transport proteins that mediate the sodium-independent transport of a wide range of amphipathic organic compounds including bile salts, steroid conjugates, thyroid hormones, anionic oligopeptides and numerous drugs (Hagenbuch & Meier 2004).

Literature References

PubMed ID	Title	Journal	Year
12883891	The SLC22 drug transporter family Koepsell, H, Endou, H	Pflugers Arch	2004
23506886	SLC27 fatty acid transport proteins Stahl, A, Anderson, CM	Mol. Aspects Med.	2013
12568659	Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins Trayhurn, P, Wood, IS	Br J Nutr	2003
25819438	Inositol transport proteins Schneider, S	FEBS Lett.	2015
16981043	Nucleotide-sugar transporters: structure, function and roles in vivo Orellana, A, Rodriguez-Furlán, C, Handford, M	Braz J Med Biol Res	2006
14624363	The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction Rolfs, A, Takanaga, H, Peng, JB, Romero, MF, Hediger, MA, Bruford, EA	Pflugers Arch	2004
18523892	Overview of the proton-coupled MCT (SLC16A) family of transporters: characterization, function and role in the transport of the drug of abuse gamma-hydroxybutyric acid Morris, ME, Felmlee, MA	AAPS J	2008
14579113	Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties Meier, PJ, Hagenbuch, B	Pflugers Arch	2004
10334869	Molecular and functional characterization of the intestinal Na+-dependent multivitamin transporter Wang, H, Leibach, FH, Ganapathy, V, Huang, W, Devoe, LD, Prasad, PD, Fei, YJ	Arch Biochem Biophys	1999
7989337	Cloning and functional expression of a urea transporter from human bone marrow cells Olives, B, Cartron, JP, Bailly, P, Rousselet, G, Hediger, MA, Neau, P, Ripoche, P	J Biol Chem	1994
15715662	Molecular characterization of the family of choline transporter-like proteins and their splice variants O'Regan, S, Meunier, FM, Ruat, M, Traiffort, E	J Neurochem	2005
19164095	Analysis and update of the human solute carrier (SLC) gene superfamily Nebert, DW, He, L, Vasiliou, K	Hum Genomics	2009
16211368	Molecular properties of the SLC13 family of dicarboxylate and sulfate transporters Pajor, AM	Pflugers Arch	2006
17439925	Metal transporters in intestine and brain: their involvement in metal-associated neurotoxicities Maerten, A, Kim, Y, Olivi, L, Bressler, JP, Cheong, JH, Bannon, D	Hum Exp Toxicol	2007
12719981	Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6 Quick, MW, Reith, ME, Chen, NH	Pflugers Arch	2004
9096318	Expression cloning and characterization of a cDNA encoding a novel membrane protein required for the formation of O-acetylated ganglioside: a putative acetyl-CoA transporter Fukuda, M, Kanamori, A, Sasaki, K, Stallcup, WB, Hirabayashi, Y, Nakayama, J, Fukuda, MN	Proc Natl Acad Sci U S A	1997