Biomedical Engineering Reference
In-Depth Information
14
Neurotransmitter Transporters:
Structure and Function
Claus J. Loland and Ulrik Gether
CONTENTS
14.1 Introduction ......................................................................................................................... 225
14.2 Neurotransmitter Transporters Belonging to the SLC6 Family ......................................... 227
14.2.1 Structures and Mechanisms of SLC6 Transporters............................................... 228
14.2.2 The Binding Sites for Na
+
and Cl
−
: Importance in Substrate Binding
and Translocation................................................................................................... 231
14.2.3 Substrate Specii city and Binding Sites in SLC6
Neurotransmitter Transporters............................................................................... 232
14.3 Drugs Targeting Biogenic Amine Transporters: Specii city, Use, and Molecular
Mechanisms of Action ........................................................................................................ 233
14.3.1 Cocaine, Benztropine, and Other Tropane Class Inhibitors .................................. 233
14.3.2 Amphetamine and Other Nonendogenous Substrates ........................................... 236
14.3.3 Antidepressants...................................................................................................... 236
14.3.4 Other Biogenic Amine Transporter Inhibitors....................................................... 237
14.4 Inhibitors of Glycine and GABA Transporters: Specii city, Use, and Molecular
Mechanism of Action .......................................................................................................... 237
14.5 Conclusion........................................................................................................................... 238
Further Readings ............................................................................................................................ 238
14.1 INTRODUCTION
The transport of solutes across membranes is of fundamental importance for all living organisms and
is mediated via specii c integral membrane proteins. The transport processes are often energetically
coupled, either directly through the hydrolysis of ATP by the transport protein itself or indirectly by
the use of transmembrane ion gradients that enable the transport of the substrate against its concentration
gradient. A vast amount of different transport proteins are found in both prokaryotic and eukaryotic
organisms, transporting everything from nutrients and metabolites to ions, drugs, proteins, toxins, and
transmitter molecules. If ion channels (see Chapter 13) are excluded, major classes of transport proteins
in humans encompass ATP-driven ion pumps (e.g., the ubiquitously expressed Na-K ATPase),
ATP-binding cassette (ABC) transporters (e.g., the cystic i brosis transmembrane conductance regulator
and the multidrug resistance transporter
p
-glycoprotein), cytochrome B-like proteins, aquaporins
(water transporters), and the solute carrier superfamily (SLC) (http://www.bioparadigms.org).
The immense functional heterogeneity among transporters is illustrated by the fact that the SLC
gene family alone consists of nothing less than 46 different subfamilies (http://www.bioparadigms.
org/slc/menu.asp). These include several types of plasma membrane transporters, such as, high-
afi nity glutamate transporters (SLC1), sodium-glucose cotransporters (SLC5), sodium-coupled
neurotransmitter transporters (SLC6), and a variety of ion exchangers (SLC8 + 9 + 24). The SLC
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