Regulation of monoamine transporters: Influence of psychostimulants and therapeutic antidepressants

Abstract

A BSTRACT Synaptic neurotransmission in the central nervous system (CNS) requires the precise control of the duration and the magnitude of neurotransmitter action at specifi c molecular targets. At the molecular level, neurotransmitter signaling is dynamically regulated by a diverse set of macromolecules including biosynthetic enzymes, secretory proteins, ion channels, pre-and postsynaptic receptors and transporters. Monoamines, 5-hydroxytryptamine or serotonin (5-HT), norepinephrine (NE), and dopamine (DA) play an important modulatory role in the CNS and are involved in numerous physiological functions and pathological conditions. Presynaptic plasma membrane transporters for 5-HT (SERT), NE (NET), and DA (DAT), respectively, control synaptic actions of these monoamines by rapidly clearing the released amine. Monoamine transporters are the sites of action for widely used antidepressants and are high affi nity molecular targets for drugs of abuse including cocaine, amphetamine, and 3,4-methylenedioxymetamphetamine (MDMA) " Ecstasy. " Monoamine transporters also serve as molecular gateways for neurotoxins. Emerging evidence indicates that regulation of transporter function and surface expression can be rapidly modulated by " intrinsic " transporter activity itself, and antidepressant and psychostimulant drugs that block monoamine transport have a profound effect on transporter regulation. Therefore, disregulations in the functioning of monoamine transporters may underlie many disorders of transmitter imbalance such as depression, attention defi cit hyperactivity disorder, and schizophrenia. This review integrates recent progress in understanding the molecular mechanisms of monoamine transporter regulation, in particular, posttranscriptional regulation by phosphorylation and traffi cking linked to cellular protein kinases, protein phosphatases, and transporter interacting proteins. The review also discusses the possible role of psychostimulants and antidepressants in infl uencing monoamine transport regulation.K EYWORDS: phosphorylation , traffi cking , interacting proteins , substrates , and ligands NEUROBIOLOGY OF MONOAMINE TRANSPORTERSThe catecholamines dopamine (DA) and norepinephrine (NE) derived from tyrosine and the indolamine 5-hydroxytryptamine or serotonin (5-HT) derived from tryptophan, packaged into synaptic vesicles and released into synapse in response to depolarizing stimuli, activate pre-and postsynaptic receptors and elicit synaptic responses. Presynaptic plasma membrane transporters for 5-HT (SERT), NE (NET), and DA (DAT), respectively, control synaptic actions of these monoamines by rapidly clearing the released amine, thereby dictating the kinetics of postsynaptic responses and receptor desensitization. Drugs that modulate the activity of biogenic monoamine transporters produce profound behavioral effects, leading to their therapeutic use in depression, obsessive-compulsive disorder, and other mental diseases and also to their abuse as stimulants. SERTAltered serotonergic neurotransmission and s...

Transmembrane Domain 6 of the Human Serotonin Transporter Contributes to an Aqueously Accessible Binding Pocket for Serotonin and the Psychostimulant 3,4-Methylene Dioxymethamphetamine

“…2). It must be noted, however, that further investigation of this phenomenon revealed this stimulation to be quite variable, suggesting that other factors, such as the substrate-dependent phosphorylation state of the transporter (47,48), may contribute to the effect. Once again, MTSEA-biotinylation experiments were less conclusive in these analyses, with MDMA pretreatment demonstrating nonsignificant reductions in biotinylation at S336C and nonsignificant enhancements in biotinylation at I333C (data not shown).…”

Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity

“…The activity of serotonergic pathways is critically regulated by the reuptake of 5-HT via the plasma membrane serotonin transporter (SERT), a member of the Na ϩ /Cl Ϫ -dependent transporter family (SLC6) (1,2). SERT is of major pharmacological and clinical interest inasmuch as it represents the primary target of several widely prescribed antidepressants, including the selective [5-hydroxytryptamine (5-HT)] reuptake inhibitors, citalopram and paroxetine (2)(3)(4).…”

“…The activity of serotonergic pathways is critically regulated by the reuptake of 5-HT via the plasma membrane serotonin transporter (SERT), a member of the Na ϩ /Cl Ϫ -dependent transporter family (SLC6) (1,2). SERT is of major pharmacological and clinical interest inasmuch as it represents the primary target of several widely prescribed antidepressants, including the selective [5-hydroxytryptamine (5-HT)] reuptake inhibitors, citalopram and paroxetine (2)(3)(4). Moreover, altered SERT expression or function has been suggested not only in depression, but also in anxious and obsessive-compulsive states, disorders that can likewise be improved by treatment with selective 5-HT reuptake inhibitors (4)(5)(6).…”

Calcineurin Interacts with the Serotonin Transporter C-Terminus to Modulate Its Plasma Membrane Expression and Serotonin Uptake

“…These include a complex combination of phosphorylation events on SERT Ser, Thr, and Tyr residues and SERT association with accessory/scaffolding proteins (Steiner et al, 2008;Zhong et al, 2012). Many SERT partners have been identified by means of two-hybrid screens and/or coimmunoprecipitation, often based on their previously described interactions with other SLC6 family transporters (Bauman et al, 2000;Haase et al, 2001;Jess et al, 2002;Carneiro and Blakely, 2006;Müller et al, 2006;Ahmed et al, 2008;Carneiro et al, 2008;Steiner et al, 2009). Proteomics strategies have also been successfully used to identify proteins interacting with SERT C terminus, in line with the importance of this domain in the localization and activity of SERT (Larsen et al, 2006).…”

“…We found that SERT interacts with both the catalytic and regulatory subunits of calcineurin (CaN), a Ca 2ϩ -calmodulin-activated protein phosphatase enriched in brain, which has been involved in synaptic plasticity and in the mechanism of action of SSRI antidepressants (Mansuy, 2003;Crozatier et al, 2007;Baumgärtel and Mansuy, 2012). These experiments were complemented by a series of in vitro and in vivo studies to determine the impact of CaN activity and CaN/SERT interaction upon 5-HT transport via SERT.…”