Transport of bile salts and organic acids, metal ions and amine compounds (Homo sapiens)
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Description
SLC transporters described in this section transport bile salts, organic acids, metal ions and amine compounds.
Myo-Inositol is a neutral cyclic polyol, abundant in mammalian tissues. It 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. Three members of the glucose transporter gene family encode inositol transporters (SLC2A13, SLC5A3 and SLC5A11) (Schneider 2015).
Five human SLC13 genes encode sodium-coupled sulphate, di- and tri-carboxylate transporters typically located on the plasma membrane of mammalian cells (Pajor 2006).
The SLC16A gene family encode proton-linked monocarboxylate transporters (MCT) which mediate the transport of monocarboxylates such as lactate and pyruvate, major energy sources for all cells in the body so their transport in and out of cells is crucial for cellular function (Morris & Felmlee 2008).
The transport of essential metals and other nutrients across tight membrane barriers such as the gastrointestinal tract and blood-brain barrier is mediated by metal-transporting proteins (encoded by SLC11, SLC30, SLC31, SLC39, SLC40 and SLC41). They can also regulate metals by efflux out of cells and cellular compartments 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. The proteins mediate transport of GABA (gamma-aminobutyric acid), norepinephrine, dopamine, serotonin, glycine, taurine, L-proline, creatine and betaine (Chen et al. 2004).
Carrier-mediated urea transport allows rapid urea movement across the cell membrane, which is particularly important in the process of urinary concentration and for rapid urea equilibrium in non-renal tissues. Two carriers exist in humans, encoded by SLC14A1 and ALC14A2 (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 ((Okuda & Haga 2000, 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). Most of this family are polyspecific transporters. Since many of these transporters are expressed in the liver, kidney and intestine, they play an important role in drug absorption and excretion. Substrates include xenobiotics, drugs, and endogenous amine compounds (Koepsell & Endou 2004). View original pathway at Reactome.
Myo-Inositol is a neutral cyclic polyol, abundant in mammalian tissues. It 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. Three members of the glucose transporter gene family encode inositol transporters (SLC2A13, SLC5A3 and SLC5A11) (Schneider 2015).
Five human SLC13 genes encode sodium-coupled sulphate, di- and tri-carboxylate transporters typically located on the plasma membrane of mammalian cells (Pajor 2006).
The SLC16A gene family encode proton-linked monocarboxylate transporters (MCT) which mediate the transport of monocarboxylates such as lactate and pyruvate, major energy sources for all cells in the body so their transport in and out of cells is crucial for cellular function (Morris & Felmlee 2008).
The transport of essential metals and other nutrients across tight membrane barriers such as the gastrointestinal tract and blood-brain barrier is mediated by metal-transporting proteins (encoded by SLC11, SLC30, SLC31, SLC39, SLC40 and SLC41). They can also regulate metals by efflux out of cells and cellular compartments 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. The proteins mediate transport of GABA (gamma-aminobutyric acid), norepinephrine, dopamine, serotonin, glycine, taurine, L-proline, creatine and betaine (Chen et al. 2004).
Carrier-mediated urea transport allows rapid urea movement across the cell membrane, which is particularly important in the process of urinary concentration and for rapid urea equilibrium in non-renal tissues. Two carriers exist in humans, encoded by SLC14A1 and ALC14A2 (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 ((Okuda & Haga 2000, 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). Most of this family are polyspecific transporters. Since many of these transporters are expressed in the liver, kidney and intestine, they play an important role in drug absorption and excretion. Substrates include xenobiotics, drugs, and endogenous amine compounds (Koepsell & Endou 2004). View original pathway at Reactome.
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DataNodes
transported by
VMAT1/2transported by
VMAT1/2transported by
NaDC1transported by
NaDC1transported by
NRAMP1transported by
NRAMP1transported by
SMIT2transported by
SMIT2conjugate
substratesconjugate
substratesSerotonin
transporterAnnotated Interactions
transported by
VMAT1/2transported by
VMAT1/2transported by
NaDC1transported by
NaDC1transported by
NRAMP1transported by
NRAMP1transported by
SMIT2transported by
SMIT2conjugate
substratesconjugate
substratesSLC16A1 encodes MCT1, a ubiquitiously expressed protein (Garcia et al. 1994). Defects in SLC16A1 are the cause of symptomatic deficiency in lactate transport (SDLT), resulting in an acidic intracellular environment and muscle degeneration (Merezhinskaya et al. 2000). Activating promotor mutations in SLC16A1 are associated with exercise-induced hyperinsulinism (EIHI), a dominantly inherited hypoglycemic disorder characterized by inappropriate insulin secretion during anaerobic exercise or on pyruvate load (Otonkoski et al. 2000). SLC16A7 encodes MCT2, a high affinity pyruvate transporter highly expressed in testis (Lin et al. 1998). SLC16A8 encodes MCT3 (Yoon et al. 1999).
Human RPE (retinal pigment epithelial) cells express two proton-coupled monocarboxylate transporters: MCT1 in the apical membrane and MCT3 in the basolateral membrane. This suggests that the coordinated activities of these two transporters could facilitate the transepithelial transport of lactate from the retina to the choroid. (Philip et al. 2003). MCTs require the binding of a single transmembrane glycoprotein (either embigin (EMB) or basigin (BSG)) for activity (Halestrap 2013).
MATE1 is primarily expressed in the kidney and liver, where it is localized to the luminal membranes of the urinary tubules and bile canaliculi. When expressed in HEK293 cells, MATE1 mediates H(+)-coupled electroneutral exchange of various drugs (Otsuka M et al, 2005). MATE2 is a human kidney-specific H+/organic cation antiporter that is responsible for the tubular secretion of cationic drugs across the brush border membranes (Masuda S et al, 2006). Substrates for both MATEs include tetraethylammonium, 1-methyl-4-phenylpyridinium, cimetidine, metformin, creatinine, guanidine and procainamide (Tanihara Y et al, 2007).
The human gene SLC11A1 encodes NRAMP1 (Kishi F, 2004; Kishi F and Nobumoto M, 1995) which can utilize the protonmotive force to mediate divalent iron (Fe2+), zinc (Zn2+) and manganese (Mn2+) influx to or efflux from phagosomes.
The human gene SLC39A14 encodes the zinc transporter ZIP14. This protein is ubiquitously expressed with higher expression seen in heart, liver and pancreas. ZIP14 is localized to the plasma membrane and mediates zinc influx into cells (Taylor KM et al, 2005).
The human gene SLC40A1 encodes the metal transporter protein MTP1 (aka ferroportin or IREG1). This protein resides on the basolateral membrane of enterocytes and mediates ferrous iron efflux into the portal vein (Schimanski et al. 2005). MTP1 colocalizes with hephaestin (HEPH) which stablizes MTP1 and is necessary for the efflux reaction to occur (Han & Kim 2007, Chen et al. 2009). As well as the dudenum, MTP1 is also highly expressed on macrophages (where it mediates iron efflux from the breakdown of haem) and the placenta (where it may mediate the transport of iron from maternal to foetal circulation). It is also expressed in muscle and spleen.
The human gene SLC39A2 encodes the zinc transporter hZIP2. It is expressed exclusively in prostate and uterine epithelial cells and mediates zinc transport into cells (Gaither LA and Eide DJ, 2000).
Normal prostate cells have the ability to accumulate high levels of zinc. In prostate cancer, hZIP1-3 transporters are down-regulated and the cells lose the ability to accumulate zinc. Zinc plays a role as a tumour-suppressing agent thus prostate cells can become cancerous. Silencing of the genes that express hZIP1-3 transporters is a required event for malignancy (Costello LC et al, 1999; Desouki MM et al, 2007).
The human gene SLC39A4 encodes the zinc transporter hZIP4 (Kury S et al, 2002). The role of zinc in tumour progression is complicated and, subsequently, so are the role of ZIP transporters. For example, ZIP4 can actually enhance cancer progression (Li M et al, 2007; Li M et al, 2009). Defects in SLC39A4 result in the inherited condition acrodermatitis enteropathica (AE) results from defective absorption of dietary zinc from the duodenum and jejunum. Clinical features include growth retardation, immune system dysfunction, severe dermatitis and mental disorders (Wang K et al, 2002).
SLC6A1 encodes a sodium- and chloride-dependent GABA transporter 1, GAT1, which is the predominant GABA transporter in brain. It is widely distributed in the brain and co-localized to GABAergic neurons (Nelson H et al, 1990). SLC6A13 encodes a sodium- and chloride-dependent GABA transporter 2, GAT2, which is localized to GABAergic neurons in the brain. It is also found in retina, liver and kidney (Christiansen B et al, 2007). SLC6A11 encodes a sodium- and chloride-dependent GABA transporter 3, GAT3. It is expressed in the brain and localizes to GABAergic neurons (Borden LA et al, 1994).
CTL1 is broadly expressed on leukocytes and endothelial cells (Wille et al. 2001). CTL2 is highly expressed in human inner ear and is the target of antibody-induced hearing loss (Nair et al. 2004).
OAT1-3 transport organic anions such as p-aminohippurate and drugs such as cimetidine and acyclovir. This transport is is coupled with an efflux of one molecule of endogenous dicarboxylic acid such as alpha-ketoglutarate (2-oxoglutarate). OAT2 is classified as both a transporter of organic anions and sulphate conjugates.
SLC16A1 encodes MCT1, a ubiquitiously expressed protein (Garcia et al. 1994). Defects in SLC16A1 are the cause of symptomatic deficiency in lactate transport (SDLT), resulting in an acidic intracellular environment and muscle degeneration (Merezhinskaya et al. 2000). Activating promotor mutations in SLC16A1 are associated with exercise-induced hyperinsulinism (EIHI), a dominantly inherited hypoglycemic disorder characterized by inappropriate insulin secretion during anaerobic exercise or on pyruvate load (Otonkoski et al. 2000). MCT1 requires the binding of a single transmembrane glycoprotein (basigin, BSG) for activity (Halestrap 2013).
Serotonin
transporter