Transporter substrate specificity

Type of Transporter Substrate Specificity Tissue Regjon/Cell Type Inhibitors... 

Substrate specificity is determined by high affinity for the cognate neurotransmitter substrate. However, low affinity uptake does also have a part in the clearance of transmitters from the interstitial space (e.g., in uptake mediated by the extraneuronal monoamine transporter, EMT) and in the intestinal absoiption of glycine and glutamate. It is obvious that there is an evolutionary relation of neurotransmitter transporters and amino acid and cation transporters in epithelia. 

VMAT1 is expressed in the adrenal medulla, by small intensely fluorescent cells in sympathetic ganglia, and by other nonneural cells that release monoamines. In contrast, VMAT2 is expressed by neuronal populations in the nervous system. The substrate specificity for the two isoforms is similar, but VMAT2 has a somewhat higher apparent affinity for all monoamines than VMAT1. In addition, only VMAT2 appears able to transport histamine, consistent with its expression by mast cells. 

Facilitated transport combines some properties of both mechanisms discussed above. This type of transport is carrier mediated so that there is substrate specificity, a transport maximum, and competitive inhibition. However, facilitated transport is not energy-dependent and is unable to transport a substrate against a concentration gradient. 

Changes in transporter proteins by high-frequency genetic mutation mechanisms, while maintaining transport activity, helps to evade the host s immune response, and in cases where the substrate specificity is changed, helps the microorganism to adapt to new iron sources. 

Measurement of absorption can be complicated by efflux mechanisms. It is clear that many compounds are actively transported back into the GIT, into the bile or into the urine by efflux proteins. In the case of those in the GIT these may have an impact on the apparent absorption of a compound. Some understanding of the substrate specificity for one of these proteins, P-glycoprotein, is becoming apparent [8, 9], but currently the understanding is limited. At the moment there are no published reliable methods either in vivo or in vitro for predicting the importance of efflux mechanisms for a particular compound in man [10-12],... 

Surendran, N., et al. Evidence for overlapping substrate specificity between large neutral amino acid (LNAA) and dipeptide (hPEPTl) transporters for PD 158473, an NMDA antagonist. Pharm. Res. 1999, 16, 391-395. 

Busch, A. E., et al. Electrogenic properties and substrate specificity of the polyspecific rat cation transporter rOCTl. /. Biol. Chem. 1996, 271, 32599-32604. 

Kramer, W., et al. Substrate specificity of the ileal and the hepatic Na(+)/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters. J. Lipid Res. 1999, 40, 1604-1617. 

P. J., Hagenbuch, B., Localization of organic anion transporting polypeptide 4 (Oatp4) in rat liver and comparison of its substrate specificity with Oatpl, Oatp2 and Oatp3, Pfliigers Arch. 2001, 443, 188-195. 

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