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Trang 5Natalie R Sealover and Eric L Barker
Abstract The monoamine neurotransmitters control a variety of functions
includ-ing movement, appetite, mood, reward, and memory The monoamine transporters are responsible for the termination of synaptic signaling by removing neurotrans-mitters from the synaptic cleft Altered monoaminergic transporter function has been implicated in the pathology of disease states such as depression, anxiety, addiction, autism, Parkinson’s disease, and attention deficit hyperactivity disorder (ADHD) This review considers the mechanism of transporter action and reg-ulation of transporter function The implications of transporter polymorphisms are also addressed Finally, a brief overview is presented that highlights impor-tant findings as well as existing problems that need to be considered in future studies.
Keywords Dopamine transporter · Norepinephrine transporter · Serotonin trans-porter · Polymorphism · Attention deficit hyperactivity disorder · Parkinson’s disease · Addiction · Anxiety · Depression · Autism
Abbreviations
β-CIT 2 β-carbomethoxy-3β-(4-iodophenyl) tropane
nor- β-CIT N-(2-fluoroethyl)-2
β-carbomethoxy-3β-(4-iodophenyl)-nortropane
LeuTAa Aquifex aeolicus leucine transporter
E.L Barker (B)
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47906, USA
e-mail: barkerel@purdue.edu
169
J.P Blass (ed.), Neurochemical Mechanisms in Disease,
Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_6,
C
Springer Science+Business Media, LLC 2011
Trang 6170 N.R Sealover and E.L Barker
MDMA, “ecstasy” 3,4-methylenedioxymethamphetamine
β-PMA Phorbol 12-myristate13-acetate
Contents
1 Introduction to Monoamine Transporters . 171
1.1 The Monoamine Transporter Family . 171
1.2 Neuroanatomy . 172
1.3 Physiological Functions . 173
1.4 Structure and Transport Mechanism . 173
1.5 Vesicular Monoamine Transporters . 175
2 Regulation of Plasma Membrane Monoamine Transporters . 175
3 Transporter Gene Polymorphisms . 177
3.1 NET . 177
3.2 DAT . 178
3.3 SERT . 179
4 Addiction . 180
4.1 Psychostimulant Addiction . 180
4.2 Alcoholism . 181
5 Anxiety and Depression . 182
6 Autism . 184
7 Parkinson’s Disease (PD) . 185
8 Important Findings and the Need for Future Studies . 185
References . 186
Trang 71 Introduction to Monoamine Transporters
1.1 The Monoamine Transporter Family
Synaptic transmission requires the release of neurotransmitters into the extracellular space to bind pre-or postsynaptic receptors, conveying a chemical message to nerve cells (Torres et al., 2003a ) Termination of this signaling occurs rapidly by uptake of the released neurotransmitter into the presynaptic cell by high-affinity neurotrans-mitter transporters The clearance of the monoamines dopamine, norepinephrine, and serotonin occurs via the dopamine transporter (DAT), norepinephrine trans-porter (NET), and serotonin transtrans-porter (SERT), respectively (Torres et al., 2003a )
Fig 1 General model of the release of vesicular neurotransmitter stores in response to cellular
depolarization and the reuptake of the neurotransmitters by the monoamine transporters Cytosolic neurotransmitters are taken into vesicles by VMAT and stored until the cell becomes depolarized, causing these vesicular stores to fuse with the plasma membrane and release the neurotransmitters into the synaptic cleft Neurotransmitters in the synaptic cleft are available to bind pre- or postsy-naptic receptors Termination of signaling occurs when the neurotransmitters are taken back into the presynaptic cell by the monoamine transporters
Trang 8172 N.R Sealover and E.L Barker (Fig 1 ) These monoamine transporters belong to the SLC6 gene family of Na+-Cl– -coupled neurotransmitter transporters that is also referred to as the neurotransmitter sodium symporter (NSS) family (Chen et al., 2004 ) In addition to the monoamine transporters, the NSS family includes subfamilies of transporters for GABA, amino acids, creatine, and the osmolytes betaine and taurine (Chen et al., 2004 ).
1.2 Neuroanatomy
In the brain, monoamine transporters are found on neurons that contain their respec-tive neurotransmitter (Torres et al., 2003a ) For example, neuronal cells that produce dopamine are localized in the substantia nigra, ventral tegmental area, and hypotha-lamus (Lin and Madras, 2006 ) The processes of dopaminergic neurons extend into the caudate nucleus, putamen, nucleus accumbens, and prefrontal cortex (Lin and Madras, 2006 ) Serotonergic neurons are located in the raphe nuclei of the brainstem and project into the cortex, thalamus, basal ganglia, hippocampus, and amygdala (Jacobs and Azmitia, 1992 ) Norepinephrine-producing neurons are found primarily
in the locus coeruleus and raphe nuclei with moderate levels in the hypothalamus, midline thalamic nuclei, and the bed nucleus of the stria terminalis (Torres et al.,
2003a ; Donnan et al., 1991 ) (Fig 2 ).
Monoamine transporters are also located in peripheral areas of the body Eisenhofer and colleagues demonstrated that DAT is present in the stomach, pan-creas, and kidney (Eisenhofer, 2001 ) NET is expressed in sympathetic peripheral neurons, the adrenal medulla, endothelial cells of the lung, and the placenta (Eisenhofer, 2001 ) SERT has been found in platelets (Talvenheimo and Rudnick,
1980 ), the intestinal tract (Wade et al., 1996 ), placenta (Padbury et al., 1997 ; Balkovetz et al., 1989 ), and in chromaffin cells of the adrenal gland (Schroeter
et al., 1997 ) Reuptake by the monoamine transporters is the primary mechanism
Fig 2 (a) Location of serotonergic neurons and their projections in the human brain (b) Location
of noradrenergic neurons and their projections in the human brain (c) Location of dopaminergic
neurons and their projections in the human brain
Trang 9of terminating monoaminergic neurotransmitter signaling in the central nervous system and periphery.
1.3 Physiological Functions
The monoamine transporters are involved in the regulation of many physiological functions DAT has been implicated in addiction and reward response, move-ment, cognition, and memory (Greengard, 2001 ) Altered dopaminergic regulation
is involved in depression, suicide, anxiety, aggression, schizophrenia, attention defict hyperactivity disorder (ADHD), and Parkinson’s disease (Jayanthi and Ramamoorthy, 2005 ; Gainetdinov and Caron, 2003 ) SERT is involved in the reg-ulation of appetite, libido, mood, anxiety, fear, reward, aggression, and memory (Barnes and Sharp, 1999 ) Disrupted serotonergic function has been implicated
in depression, suicide, impulsive violence, autism, and alcoholism (Jayanthi and Ramamoorthy, 2005 ) NET plays an important role in arousal, mood, aggression, addiction, and attention, as well as in thermal and cardiac regulation (Jayanthi and Ramamoorthy, 2005 ; Howell and Kimmel, 2008 ) Alteration of the noradrengeric system can result in cardiac disease and psychiatric disorders including depression and anxiety (Jayanthi and Ramamoorthy, 2005 ).
1.4 Structure and Transport Mechanism
The monoamine transporters contain 12 alpha helical transmembrane helices (TMHs) with a putative large extracellular loop between TMHs III and IV with potential glycosylation sites (Melikian et al., 1996 , 1994 ) (Fig 3 ) The amino and carboxy termini are located intracellularly and contain putative phosphorylation sites (Torres et al., 2003a ) Uptake of the monoamines by their respective trans-porters utilizes an ion gradient generated by the plasma membrane Na+/K+ATPase (Torres et al., 2003a ) NET and SERT are thought to translocate one Na+ion and one
Cl–ion with the substrate per transport cycle, whereas DAT is predicted to transport two Na+ions and one Cl–ion with its substrate (Torres et al., 2003a ).
The alternating access transport model has been used to describe the mechanism
by which substrates are transported across the membrane via the monoamine trans-porters (Forrest et al., 2008 ) This model postulates that the transporter can exist
in at least two conformations These conformations include an extracellularly fac-ing form that is open to the extracellular environment and can bind substrate and
Na+ and Cl– ions (Forrest et al., 2008 ) An intracellularly facing form allows the release of substrate into the cell and the binding of the countertransported K+ ion
to reverse the conformation of the transporter (Forrest et al., 2008 ) The alternating access model is supported by recent crystal structures of other transporters (Weyand
et al., 2008 ; Faham et al., 2008 ) Two additional conformations of these transporters have also been described A closed–closed conformation is predicted that prevents accessibility of substrate and ions from either side of the transporter This closed– closed conformation was observed in the crystal structure of a leucine transporter
Trang 10174 N.R Sealover and E.L Barker
Fig 3 Schematic representation of the predicted topology of the monoamine transporters based
on the crystallization of LeuTAa (Yamashita et al.,2005) The representation demonstrates how extracellular Na+, Cl–, and substrate are exchanged for intracellular K+ The putative phosphory-lation sites on the N-terminus and C-terminus are shown along with predicted glycosyphosphory-lation sites between TMH III and TMH IV This figure was adapted from Yamashita et al (2005)
from Aquifex aeolicus (LeuTAa), a bacterial homologue of the NSS transporter fam-ily (Yamashita et al., 2005 ) The closed–closed conformation has closed intra- and extracellular gates and may serve as an intermediate between the extracellularly and intracellularly facing states Another conformation is predicted to have open intra-and extracellular gates In this conformation the transporter is predicted to operate
in a channel mode, allowing substrate molecules and ions to pass through the trans-porter quickly without an opening and closing of the gates for each transport cycle (Torres et al., 2003a ).
Comprehensive understanding of the mechanism of monoamine transport has been hampered by the lack of a crystal structure of these membrane transporters.
As mentioned above, in 2005, LeuTAa was crystallized (Yamashita et al., 2005 ) This structure and the cocrystallization of LeuTAawith the tricyclic antidepressants (TCAs) have provided several clues about the putative structure of the monoamine transporters (Singh et al., 2007 ; Yamashita et al., 2005 ; Zhou et al., 2007 ) The LeuTAa structures reveal binding sites for substrate and Na+ ions located about halfway through the pore of the protein, interacting with TMHs III and VIII and the unwound regions of TMHs I and VI (Singh et al., 2007 ) The protein structure shows TMHs I through V are related to VI through X by a pseudo twofold axis in the membrane plane (Yamashita et al., 2005 ) Cocrystallization studies with the TCAs have identified a putative binding pocket in LeuT that places the TCA binding