Solute carrier transporters

Figure 15.1 Schematic illustration of the extended phase concept during drug elimination in the kidney and liver. Phase 0 = uptake of drugs from the blood into the hepatocytes or proximal tubule epithelial cells. This uptake is mediated by transport proteins belonging to the SLC (solute carrier) transporter superfamily. Phase I and...

As noted in Chapter 1, several large families of transport proteins have been identified. The most important of these are the ABC (ATP-Binding Cassette) and SLC (SoLute Carrier) transporter families. As indicated by the name, the ABC carriers utilize ATP for transport. The SLC proteins are cotransporters and in most cases, use the movement of sodium down its concentration gradient as the energy source. Under some circumstances, they also transport transmitters in the reverse direction in a sodium-independent fashion. 

The barrier to paracellular diffusion potentially isolates the brain from many essential polar nutrients such as glucose and amino acids that are required for metabolism and, therefore, the BBB endothelium must contain a number of specific solute carriers (transporters) to supply the CNS with its requirements for these substances. The formation of tight junctions essentially confers on the BBB the properties of a continuous cell membrane, both in terms of the diffusional characteristics imposed by the lipid bilayer, and the directionality and properties of the specific transport proteins, and solute carriers (SLC) that are present in the cell membrane. Examples of BBB solute carriers (SLC transporters) are listed in Table 27.2. 

A second important family of drug transport proteins are the solute carrier transporters (SLC). SLC proteins play important physiological roles in the transport of nutrients and drugs. SLCs function by one of several mechanisms including facilitated, ion-coupled, and ion-exchange transport. Within each of the 43 SLC subfamilies that have been identified, transporters have at least 20 to 25% amino acid sequence identity. Table 9.3 lists the SLC transport families that play... 

Solute Carrier Transporters SLClOAl NTCP Liver... 

Membrane-soluble carrier molecules can bind an ion from aqueous solution to create a charged ion/carrier complex within the membrane. This soluble ion then moves down a concentration or electrical gradient to the opposite interface where the ion is released to that solution. Carrier transport is modeled in four kinetic steps (1) the carrier absorbs an ion from solution 1 (2) the ion/carrier complex moves down its gradient to the opposite interface ... 

Geier, E.G., Chen, E.C., Webb, A., et al., 2013. Profiling solute carrier transporters in the human blood-brain barrier. Clin. Pharmacol. Ther. 94, 636-639. 

Nishimura, M., and S. Naito, 2008. Ussue-speeifie mRNA expression profiles of human solute carrier transporter superfamilies. Drug Metab. Phaimacokinet. 23,22-44. 

Fatty acid transport protein paralogues 1-6 FATP 1-6 Gene symbols SLC27A1-6 Solute carrier family 27A Very long-chain acyl-CoA synthetase VLCS... 

Neurotransmitter transporters Members of the family of solute carriers Products of the (solute carrier) SLC1, SLC6, SLC17, SLC18, and SLC22 gene families... 

Carrier-mediated transport is linear with mucosal solute concentration until this concentration exceeds the number of available carriers. At this point the maximal solute flux (7max) is independent of further increases in mucosal solute concentration. In the linear range of solute flux versus mucosal concentration (C), the proportionality constant is the ratio of / to the solute-carrier affinity constant (Km). This description of Michaelis-Menten kinetics is directly analogous to time changes in mass per unit volume (velocity of concentration change) found in enzyme kinetics, while here the appropriate description is the time change in solute mass per unit surface area of membrane supporting the carrier. 

Oligopeptide transporter (Solute carrier family 15, member 1 (SLC15A1))... 

SLC2 (solute carrier) superfamily consists of 12 glucose transporters (GLUT1-12) and one H+-myo-inositol cotransporter (HMIT or GLUT13). They all have 12 transmembrane segments with the N- and C-termini both on the cytoplasmic aspect and a specific N-linked oligosaccharide side-chain on either the first or fourth extracellular loop. 

In the renal epithelium, many uptake transporters are localized in the basolateral membrane and efflux transporters are localized in the apical membrane (Figure 15.2). As a result, vectorial transport of endogenous substances and of drugs from the blood into the urine is achieved. The important uptake transporters are members of the SLC22 family of solute carriers, especially the family members OCT2 and OAT2, which are highly expressed in human kidney. 

Hediger, M.A., Romero, M.F., Peng, J.B., Rolfs, A., Takanaga, H. and Bruford, E.A. (2004) The ABCs of solute carriers physiological, pathological and therapeutic implications of human membrane transport proteins. Pflugers Archiv, 447, 465-468. 

Other solute transporters (solute carrier protein [SLC]) are also expressed in the alveolus. The mRNA transcripts of glucose transporters, GLUT1, GLUT4, GLUT5 and SGLT1, have been detected in freshly isolated rat ATII cells by... 

Carriers consist of proteins that extend completely across the membrane. A solute being transported is initially bonnd to external sites on the carrier protein subsequent changes in the conformation of the protein resnlt in the transfer of the bound solnte across to the other side of the membrane where it dissociates. 

Species/Solute Carrier Internal reagent Co/Coimter transport of ion LM type Mathematical model Inference Reference... 

Step 1 the P ion, after diffusing to the feed-SLM interface, reacts with QCl (Eq. 4) forming a solute-carrier complex, QP CL ions are simultaneously released into the feed solution (coupled transport). 

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