Neurochemical Mechanisms in Disease P19 pps

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Sealover and Eric L. Barker Abstract The monoamine neurotransmitters control a variety of functions including movement, appetite, mood, reward, and memory. The monoamine transporters are responsible for the termination of synaptic signaling by removing neurotransmitters from the synaptic cleft. Altered monoaminergic transporter function has been implicated in the pathology of disease states s uch as depression, anxiety, addiction, autism, Parkinson’s disease, and attention deficit hyperactivity disorder (ADHD). This review considers the mechanism of transporter action and regulation of transporter function. The implications of transporter polymorphisms are also addressed. Finally, a brief overview is presented that highlights important findings as well as existing problems that need to be considered in future studies. Keywords Dopamine transporter · Norepinephrine transporter · Serotonin transporter · Polymorphism · Attention deficit hyperactivity disorder · Parkinson’s disease · Addiction · Anxiety · Depression · Autism Abbreviations ADHD Attention deficit hyperactivity disorder β-CIT 2β-carbomethoxy-3β-(4-iodophenyl) tropane nor-β-CIT N-(2-fluoroethyl)-2β-carbomethoxy-3β-(4-iodophenyl)- nortropane DAT Dopamine transporter GAD Generalized anxiety disorder K m Substrate affinity LeuT Leucine transporter LeuT Aa 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 170 N.R. Sealover and E.L. Barker MAOI Monoamine oxidase inhibitor MAPK Mitogen-activated protein kinase MDMA, “ecstasy” 3,4-methylenedioxymethamphetamine MPP + 1-methyl-4-phenylpyridinium NET Norepinephrine transporter NSS Neurotransmitter/sodium symporter OCD Obsessive compulsive disorder PD Parkinson’s disease PKC Protein kinase C β-PMA Phorbol 12-myristate13-acetate PP2A Protein phosphatase 2A SERT Serotonin transporter SNP Single nucleotide polymorphism SPECT Single-photon emission computed tomography SSRI Selective serotonin reuptake inhibitor TAAR1 Trace amine-associated receptor 1 TCA Tricyclic antidepressant TMH Transmembrane helice VMAT Vesicular monoamine transporter V max Transport capacity VNTR Variable number tandem repeat 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 Monoamine Transporter Pathologies 171 1 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 neurotransmitter transporters. The clearance of the monoamines dopamine, norepinephrine, and serotonin occurs via the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (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 postsynaptic receptors. Termination of signaling occurs when the neurotransmitters are taken back into the presynaptic cell by the monoamine transporters 172 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 respective neurotransmitter (Torres et al., 2003a). For example, neuronal cells that produce dopamine are localized in the substantia nigra, ventral tegmental area, and hypothalamus (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 Monoamine Transporter Pathologies 173 of 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, movement, 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 regulation 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 transporters 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 s ubstrate 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 transporters (Forrest et al., 2008). This model postulates that the transporter can exist in at least two conformations. These conformations include an extracellularly facing 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 174 N.R. Sealover and E.L. Barker Fig. 3 Schematic representation of the predicted topology of the monoamine transporters based on the crystallization of LeuT Aa (Yamashita et al., 2005). The representation demonstrates how extracellular Na + ,Cl – , and substrate a re exchanged for intracellular K + . The putative phosphorylation sites on the N-terminus and C-terminus are shown along with predicted glycosylation sites between TMH III and TMH IV. This figure was adapted from Yamashita et al. (2005) from Aquifex aeolicus (LeuT Aa ), a bacterial homologue of the NSS transporter family (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 transporter 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, LeuT Aa was crystallized (Yamashita et al., 2005). This structure and the cocrystallization of LeuT Aa with 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 LeuT Aa 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 Aa that places the TCA binding . human brain. (c) Location of dopaminergic neurons and their projections in the human brain Monoamine Transporter Pathologies 173 of terminating monoaminergic neurotransmitter signaling in the central. Barker MAOI Monoamine oxidase inhibitor MAPK Mitogen-activated protein kinase MDMA, “ecstasy” 3,4-methylenedioxymethamphetamine MPP + 1-methyl-4-phenylpyridinium NET Norepinephrine transporter NSS. disorder PD Parkinson’s disease PKC Protein kinase C β-PMA Phorbol 12-myristate13-acetate PP2A Protein phosphatase 2A SERT Serotonin transporter SNP Single nucleotide polymorphism SPECT Single-photon

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