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  • The numbers and types of

    2024-04-02

    The numbers and types of molecules needing to be transported across membranes are very large, and there is a corresponding very large and diverse number of transporters expressed throughout the body. Hundreds of proteins that have been assigned as having transporter function are broadly divided into two large groups, the solute carrier (SLC) and ATP-binding cassette (ABC) families. As new proteins are being continuously identified and assigned to these two families, the numbers are continually changing. A comprehensive review of transporters has been recently published, with active links to the web-based details of individual transporters (IUPHAR/BPS Guide to Pharmacology: http://www.guidetopharmacology.org). The SLC superfamily consists of 52 gene PF-04620110 and over 400 individual proteins. Assignment into a gene family is based on sequence similarity (sharing at least 20% identity) and likely transmembrane α-helical structures. However, members within a single family can have distinctly different functions, exemplified by the SLC22 family that includes transporters of both organic anions and cations. Furthermore, the functional selectivity or specificity of transporters can be shared by SLC families that are unrelated in the genetic sense: for example, no less than 10 different SLC families function in the accumulation of amino acids. Finally, transporters can act in concert, as exemplified by the system XC−, the cystine-glutamate antiporter that is a covalent combination of two separate transporters SLC3A2 and SLC7A11: one protein is responsible for transport function and the other for cell surface expression. The human ABC transporter proteins have been arranged into seven subfamilies, with 49 identified human ABC genes. All ABC transporters share similar structural characteristics, the most obvious being the binding site for ATP. As with the SLC transporters, individual members of the ABC transporter subfamilies may have different substrate selectivities (eg, ABCB1 for multidrug resistance and ABCB2 for peptide transport), and transport functions may be shared by members of different subfamilies (eg, ABCA3, ABCB1, and ABCC1 are all involved in multidrug resistance).
    Introduction Transporters are integral membrane solute carrier proteins that selectively bind endogenous substrates at one side of the membrane and transfer them to the opposite side. A number of neurotransmitters, including dopamine, norepinephrine, serotonin, GABA and glutamate, are substrates for selective transporters which are mostly situated on the plasma membrane of nerve endings. Plasmalemmal neurotransmitter transporters have been the object of several review articles, more than ten entirely dedicated to these proteins published in the last few years (Sitte and Freissmuth, 2010, Kristensen et al., 2011, Schousboe et al., 2011, Blakely and Edwards, 2012, Bröer and Gether, 2012, Focke et al., 2013, Pramod et al., 2013, Zhou and Danbolt, 2013, Grewer et al., 2014, Rudnick et al., 2014, Jensen et al., 2015). There is increasing evidence that neurotransmitter transporters are multitasking devices able to perform different functions under physiological, pathological and pharmacological conditions. The first function attributed to neurotransmitter transporters is reuptake into nerve terminals of the transmitters just released in the synapse. A second function consists in the ability of transporters to bind transmitters present in the cytosol and to export them extracellularly by transporter reversal. Besides uptake and carrier-mediated release, there exist functions of neurotransmitter transporters that have been so far scarcely considered. These functions consist in mediating a variety of effects dependent on ionic fluxes and currents generated by the transporters as well as on interactions of transporters with targets coexisting on the same membrane, including different neurotransmitter transporters and presynaptic receptors. These additional functions of neurotransmitter transporters are the major object of the present review article.