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1.  Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2 
eLife  2013;2:e00592.
α-Synuclein is a presynaptic protein that is implicated in Parkinson's and other neurodegenerative diseases. Physiologically, native α-synuclein promotes presynaptic SNARE-complex assembly, but its molecular mechanism of action remains unknown. Here, we found that native α-synuclein promotes clustering of synaptic-vesicle mimics, using a single-vesicle optical microscopy system. This vesicle-clustering activity was observed for both recombinant and native α-synuclein purified from mouse brain. Clustering was dependent on specific interactions of native α-synuclein with both synaptobrevin-2/VAMP2 and anionic lipids. Out of the three familial Parkinson's disease-related point mutants of α-synuclein, only the lipid-binding deficient mutation A30P disrupted clustering, hinting at a possible loss of function phenotype for this mutant. α-Synuclein had little effect on Ca2+-triggered fusion in our reconstituted single-vesicle system, consistent with in vivo data. α-Synuclein may therefore lead to accumulation of synaptic vesicles at the active zone, providing a ‘buffer’ of synaptic vesicles, without affecting neurotransmitter release itself.
eLife digest
The central nervous system coordinates many different activities by sending instructions to large numbers of cells and, simultaneously, processing all the signals that are sent back to the brain. All these messages are carried by electrical pulses that travel along chains of neurons, with neurotransmitter molecules enclosed inside synaptic vesicles conveying the messages across the synapses between neurons. A protein called α-synuclein is thought to have a role in the transport of neurotransmitter molecules across synapses, but the details of its involvement are not fully understood.
Mutations in the gene that codes for α-synuclein, and also duplications and triplications of this gene, are known to lead to an increased risk of early onset Parkinson's disease, a condition where the central nervous system degenerates. Moreover, the Lewy bodies found in the neurons of patients with Parkinson's disease contain high concentrations of α-synuclein. Again, however, none of this is fully understood.
Diao et al. have shed new light on these questions by creating synthetic vesicles to mimic what happens in real synapses, and using optical microscopy to observe the behaviour of these vesicles. They found that native α-synuclein (and another set of membrane proteins) increases the availability of synthetic vesicles at the synapse by causing them to cluster together. In a second experiment, Diao et al. showed that native α-synuclein does not decrease calcium-triggered fusion between membranes, the process that releases neurotransmitter into the synaptic cleft. In contrast, it is known that pathogenic α-synuclein aggregates directly interfere with the release of the neurotransmitter molecules. Moreover, when Diao et al. used a particular mutant form of α-synuclein that is associated with Parkinson's disease, the vesicles did not form clusters. If these results are confirmed in vivo, the role played by native α-synuclein in the central nervous system, and the connection between α-synuclein and Parkinson's disease, will be much clearer.
PMCID: PMC3639508  PMID: 23638301
Parkinson's disease; synaptic terminals; alpha-synuclein; Mouse
2.  The Science of Fibromyalgia 
Mayo Clinic Proceedings  2011;86(9):907-911.
Fibromyalgia (FM) is a common chronic widespread pain disorder. Our understanding of FM has increased substantially in recent years with extensive research suggesting a neurogenic origin for the most prominent symptom of FM, chronic widespread pain. Neurochemical imbalances in the central nervous system are associated with central amplification of pain perception characterized by allodynia (a heightened sensitivity to stimuli that are not normally painful) and hyperalgesia (an increased response to painful stimuli). Despite this increased awareness and understanding, FM remains undiagnosed in an estimated 75% of people with the disorder. Clinicians could more effectively diagnose and manage FM if they better understood its underlying mechanisms. Fibromyalgia is a disorder of pain processing. Evidence suggests that both the ascending and descending pain pathways operate abnormally, resulting in central amplification of pain signals, analogous to the “volume control setting” being turned up too high. Patients with FM also exhibit changes in the levels of neurotransmitters that cause augmented central nervous system pain processing; levels of several neurotransmitters that facilitate pain transmission are elevated in the cerebrospinal fluid and brain, and levels of several neurotransmitters known to inhibit pain transmission are decreased. Pharmacological agents that act centrally in ascending and/or descending pain processing pathways, such as medications with approved indications for FM, are effective in many patients with FM as well as other conditions involving central pain amplification. Research is ongoing to determine the role of analogous central nervous system factors in the other cardinal symptoms of FM, such as fatigue, nonrestorative sleep, and cognitive dysfunction.
PMCID: PMC3258006  PMID: 21878603
3.  Cell-type Specific Distribution of Chloride Transporters in the Rat Suprachiasmatic Nucleus 
Neuroscience  2009;165(4):1519.
The suprachiasmatic nucleus (SCN) is a circadian oscillator and biological clock. Cell-to-cell communication is important for synchronization among SCN neuronal oscillators and the great majority of SCN neurons use γ-aminobutyric acid (GABA) as a neurotransmitter, the principal inhibitory neurotransmitter in the adult central nervous system. Acting via the ionotropic GABAA receptor, a chloride ion channel, GABA typically evokes inhibitory responses in neurons via Cl− influx. Within the SCN GABA evokes both inhibitory and excitatory responses although the mechanism underlying GABA-evoked excitation in the SCN is unknown. GABA-evoked depolarization in immature neurons in several regions of the brain is a function of intracellular chloride concentration, regulated largely by the cation-chloride cotransporters NKCC1 (for chloride entry) and KCC1-4 (for chloride egress). It is well established that changes in the expression of the cation-chloride cotransporters through development determines the polarity of the response to GABA. To understand the mechanisms underlying GABA-evoked excitation in the SCN, we examined the SCN expression of cationchloride cotransporters. Previously we reported that the K+/Cl− cotransporter KCC2, a neuron-specific chloride extruder conferring GABA's more typical inhibitory effects, is expressed exclusively in vasoactive intestinal peptide (VIP) and gastrin-releasing peptide (GRP) neurons in the SCN. Here we report that the K+/Cl− cotransporter isoforms KCC4 and KCC3 are expressed solely in vasopressin (VP) neurons in the SCN whereas KCC1 is expressed in VIP neurons, similar to KCC2. NKCC1 is expressed in VIP, GRP and VP neurons in the SCN as is WNK3, a chloride-sensitive neuron-specific serine-threonine kinase which modulates intracellular chloride concentration via opposing actions on NKCC and KCC cotransporters. The heterogeneous distribution of cation-chloride cotransporters in the SCN suggests that Cl− levels are differentially regulated within VIP/GRP and VP neurons. We suggest that GABA's excitatory action is more likely to be evoked in VP neurons that express KCC4.
PMCID: PMC2815043  PMID: 19932740
circadian rhythms; GABA; KCC2; KCC3; KCC4; NKCC1; WNK3
4.  Homeostatic mechanisms in dopamine synthesis and release: a mathematical model 
Dopamine is a catecholamine that is used as a neurotransmitter both in the periphery and in the central nervous system. Dysfunction in various dopaminergic systems is known to be associated with various disorders, including schizophrenia, Parkinson's disease, and Tourette's syndrome. Furthermore, microdialysis studies have shown that addictive drugs increase extracellular dopamine and brain imaging has shown a correlation between euphoria and psycho-stimulant-induced increases in extracellular dopamine [1]. These consequences of dopamine dysfunction indicate the importance of maintaining dopamine functionality through homeostatic mechanisms that have been attributed to the delicate balance between synthesis, storage, release, metabolism, and reuptake.
We construct a mathematical model of dopamine synthesis, release, and reuptake and use it to study homeostasis in single dopaminergic neuron terminals. We investigate the substrate inhibition of tyrosine hydroxylase by tyrosine, the consequences of the rapid uptake of extracellular dopamine by the dopamine transporters, and the effects of the autoreceoptors on dopaminergic function. The main focus is to understand the regulation and control of synthesis and release and to explicate and interpret experimental findings.
We show that the substrate inhibition of tyrosine hydroxylase by tyrosine stabilizes cytosolic and vesicular dopamine against changes in tyrosine availability due to meals. We find that the autoreceptors dampen the fluctuations in extracellular dopamine caused by changes in tyrosine hydroxylase expression and changes in the rate of firing. We show that short bursts of action potentials create significant dopamine signals against the background of tonic firing. We explain the observed time courses of extracellular dopamine responses to stimulation in wild type mice and mice that have genetically altered dopamine transporter densities and the observed half-lives of extracellular dopamine under various treatment protocols.
Dopaminergic systems must respond robustly to important biological signals such as bursts, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of tyrosine hydroxylase, the dopamine transporters, and the dopamine autoreceptors.
PMCID: PMC2755466  PMID: 19740446
5.  Serotonin synthesis, release and reuptake in terminals: a mathematical model 
Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system.
We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data.
We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to experimental data. Finally, we study how the properties of the the serotonin transporter and the autoreceptors give rise to the time courses of extracellular serotonin in various projection regions after a dose of fluoxetine.
Serotonergic systems must respond robustly to important biological signals, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of the serotonin transporters and the serotonin autoreceptors. Many difficult questions remain in order to fully understand how serotonin biochemistry affects serotonin electrophysiology and vice versa, and how both are changed in the presence of selective serotonin reuptake inhibitors. Mathematical models are useful tools for investigating some of these questions.
PMCID: PMC2942809  PMID: 20723248
6.  Endocannabinoids mediate muscarine-induced synaptic depression at the vertebrate neuromuscular junction 
The European Journal of Neuroscience  2007;25(6):1619-1630.
Endocannabinoids (eCBs) inhibit neurotransmitter release throughout the central nervous system. Using the Ceratomandibularis muscle from the lizard Anolis carolinensis we asked whether eCBs play a similar role at the vertebrate neuromuscular junction. We report here that the CB1 cannabinoid receptor is concentrated on motor terminals and that eCBs mediate the inhibition of neurotransmitter release induced by the activation of M3 muscarinic acetylcholine (ACh) receptors. N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, a CB1 antagonist, prevents muscarine from inhibiting release and arachidonylcyclopropylamide (ACPA), a CB1 receptor agonist, mimics M3 activation and occludes the effect of muscarine. As for its mechanism of action, ACPA reduces the action-potential-evoked calcium transient in the nerve terminal and this decrease is more than sufficient to account for the observed inhibition of neurotransmitter release. Similar to muscarine, the inhibition of synaptic transmission by ACPA requires nitric oxide, acting via the synthesis of cGMP and the activation of cGMP-dependent protein kinase. 2-Arachidonoylglycerol (2-AG) is responsible for the majority of the effects of eCB as inhibitors of phospholipase C and diacylglycerol lipase, two enzymes responsible for synthesis of 2-AG, significantly limit muscarine-induced inhibition of neurotransmitter release. Lastly, the injection of (5Z,8Z,11Z,14Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide (an inhibitor of eCB transport) into the muscle prevents muscarine, but not ACPA, from inhibiting ACh release. These results collectively lead to a model of the vertebrate neuromuscular junction whereby 2-AG mediates the muscarine-induced inhibition of ACh release. To demonstrate the physiological relevance of this model we show that the CB1 antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide prevents synaptic inhibition induced by 20 min of 1-Hz stimulation.
PMCID: PMC1890580  PMID: 17408433
Anolis carolinensis; endocannabinoids; muscarinic; neuromuscular junction; synaptic depression
7.  Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology 
Current Neuropharmacology  2006;4(2):101-114.
The neurotransmitter serotonin (5-HT), widely distributed in the central nervous system (CNS), is involved in a large variety of physiological functions. In several brain regions 5-HT is diffusely released by volume transmission and behaves as a neuromodulator rather than as a “classical” neurotransmitter. In some cases 5-HT is co-localized in the same nerve terminal with other neurotransmitters and reciprocal interactions take place. This review will focus on the modulatory action of 5-HT on the effects of glutamate and γ-amino-butyric acid (GABA), which are the principal neurotransmitters mediating respectively excitatory and inhibitory signals in the CNS. Examples of interaction at pre-and/or post-synaptic levels will be illustrated, as well as the receptors involved and their mechanisms of action. Finally, the physiological meaning of neuromodulatory effects of 5-HT will be briefly discussed with respect to pathologies deriving from malfunctioning of serotonin system.
PMCID: PMC2430669  PMID: 18615128
Serotonin; neuromodulation; GABA; glutamate; cognition; nociception; motor control
8.  Behavioral and Immune Responses to Infection Require Gαq- RhoA Signaling in C. elegans 
PLoS Pathogens  2012;8(2):e1002530.
Following pathogen infection the hosts' nervous and immune systems react with coordinated responses to the danger. A key question is how the neuronal and immune responses to pathogens are coordinated, are there common signaling pathways used by both responses? Using C. elegans we show that infection by pathogenic strains of M. nematophilum, but not exposure to avirulent strains, triggers behavioral and immune responses both of which require a conserved Gαq-RhoGEF Trio-Rho signaling pathway. Upon infection signaling by the Gαq pathway within cholinergic motorneurons is necessary and sufficient to increase release of the neurotransmitter acetylcholine and increase locomotion rates and these behavioral changes result in C. elegans leaving lawns of M. nematophilum. In the immune response to infection signaling by the Gαq pathway within rectal epithelial cells is necessary and sufficient to cause changes in cell morphology resulting in tail swelling that limits the infection. These Gαq mediated behavioral and immune responses to infection are separate, act in a cell autonomous fashion and activation of this pathway in the appropriate cells can trigger these responses in the absence of infection. Within the rectal epithelium the Gαq signaling pathway cooperates with a Ras signaling pathway to activate a Raf-ERK-MAPK pathway to trigger the cell morphology changes, whereas in motorneurons Gαq signaling triggers behavioral responses independent of Ras signaling. Thus, a conserved Gαq pathway cooperates with cell specific factors in the nervous and immune systems to produce appropriate responses to pathogen. Thus, our data suggests that ligands for Gq coupled receptors are likely to be part of the signals generated in response to M. nematophilum infection.
Author Summary
Once infected by a pathogen the nervous and immune systems of many animals react with coordinated responses to the danger. A key question is what are the pathways by which responses to infection occur and to what extent are the same pathways involved in differing responses? Here we demonstrate that a Gαq-RhoA pathway is required for both behavioral and immune responses to infection in C. elegans. We show that Gαq-RhoA signaling is a late step in the response to infection and their site of action defines the cellular targets of signals generated internally in response to infection. One response is to move away from sites of pathogenic bacteria and Gαq-RhoA signaling acts in motorneurons to achieve this. A second response is an innate immune response where Gαq-RhoA signaling acts within cells close to sites of infection, the rectal epithelial cells, to cause major changes in their size and shape to mitigate the effects of infection. Our work demonstrates that ligands for Gq coupled GPCRs are likely to be required for response to infection. Identifying these ligands and the cells that release them will help define the mechanisms by which C. elegans recognizes pathogens and coordinates behavioral and immune responses to infection.
PMCID: PMC3280986  PMID: 22359503
9.  Astrocytes Optimize the Synaptic Transmission of Information 
PLoS Computational Biology  2008;4(5):e1000088.
Chemical synapses transmit information via the release of neurotransmitter-filled vesicles from the presynaptic terminal. Using computational modeling, we predict that the limited availability of neurotransmitter resources in combination with the spontaneous release of vesicles limits the maximum degree of enhancement of synaptic transmission. This gives rise to an optimal tuning that depends on the number of active zones. There is strong experimental evidence that astrocytes that enwrap synapses can modulate the probabilities of vesicle release through bidirectional signaling and hence regulate synaptic transmission. For low-fidelity hippocampal synapses, which typically have only one or two active zones, the predicted optimal values lie close to those determined by experimentally measured astrocytic feedback, suggesting that astrocytes optimize synaptic transmission of information.
Author Summary
Release of chemical (neurotransmitter)-filled vesicles at neuronal junctions called synapses leads to transmission of information between neurons. In a successful synaptic transmission, a voltage spike (action potential) generated by a presynaptic neuron initiates neurotransmitter vesicle release and leads to a small current in the postsynaptic neuron. For many synapses in the central nervous system, the probability that a neurotransmitter vesicle is released in response to an action potential is conspicuously small, raising the question whether transmission failures can in any way prove advantageous. Apart from “induced vesicle release” (in response to an action potential), vesicles are also released asynchronously (in absence of an action potential). An induced release probability that is too small samples the information poorly, as many of the incoming action potentials do not result in a postsynaptic current response. Maximizing induced release in order to maximize information transmission at a synapse is accompanied by the exceptionable outcome of increased asynchronous release; in addition, both these releases draw from the same neurotransmitter resource pool. A large release rate thus comprising both induced as well as asynchronous release of vesicles can suppress synaptic transmission via either depletion of neurotransmitter resources or desensitization of postsynaptic receptors. In this paper, we propose that the competing dynamics of induced and asynchronous vesicle release gives rise to an optimal release probability. Further, by comparing experimental data of astrocyte-enhanced synaptic transmission with simulations, we argue that synapses enwrapped by astrocytes operate close to our predicted optimum. This optimality is achieved through a closed-loop control circuitry that involves the presynaptic neuron and the synaptic astrocyte.
PMCID: PMC2390854  PMID: 18516277
10.  Dominance of P/Q-type calcium channels in depolarization-induced presynaptic fm dye release in cultured hippocampal neurons☆ 
Neuroscience  2013;253(100):330-340.
•We analyzed depolarization-induced synaptic FM dye release in hippocampal neurons.•We pharmacologically isolated the contribution of voltage-gated Ca2+ channels.•85% of synapses utilize N- and P/Q-type channels, 15% only P/Q-type channels.•In both groups of synapses release kinetics are determined by P/Q-type channels.•We propose a more direct coupling of P/Q-type channels to synaptic release.
Neurotransmitter release probability is related by high power to the local concentration of calcium in presynaptic terminals, which in turn is controlled by voltage-gated calcium channels. P/Q- and N-type channels trigger synaptic transmission in the majority of neurons of the central nervous system. However, whether and under which conditions both channel types act cooperatively or independently is still insufficiently understood. Previous studies suggested either a dominance of N- or P/Q-type channels, or a synergistic action of both channels, depending on the experimental paradigms. Thus, to provide insight into the properties of neurotransmitter release in cultured mouse hippocampal neurons, we used quantitative analysis of FM dye release from presynaptic boutons induced by high potassium membrane depolarization. Increasing extracellular potassium concentrations revealed a sigmoid dependence of FM dye release to the stimulation strength. Individual and combined application of the P/Q- and N-type channel-specific blockers ω-agatoxin-IVA and ω-conotoxin-GVIA, respectively, allowed us to specifically isolate the contribution of both channel types to release triggered with 40 mM KCl. Analysis of the release kinetics and the fractional release amplitude demonstrate that, whereas in only 15% of the synapses release depended exclusively on P/Q-type channels, the majority of synapses (85%) contained both N- and P/Q-type channels. Nevertheless, the kinetics of FM dye release in synapses containing both channel types was determined by the P/Q-type channels. Together, our data suggest a more direct coupling of P/Q-type channels to synaptic release compared to N-type channels, which may explain the high prevalence of neurological P/Q-type channelopathies.
PMCID: PMC3824072  PMID: 24012836
A, release amplitude; Aga, ω-agatoxin-IVA; CaV, voltage-gated Ca2+ channel; CTx, ω-conotoxin GVIA; DIV, days in vitro; [K+], extracellular potassium concentration; Rf, fractional release; τ, release time constant; voltage-gated Ca2+ channels; synapse function; N-type; P/Q-type; neurotransmitter release; calcium channel physiology
11.  Intranasal exposure to manganese disrupts neurotransmitter release from glutamatergic synapses in the central nervous system in vivo 
Neurotoxicology  2012;33(5):996-1004.
Chronic exposure to aerosolized manganese induces a neurological disorder that includes extrapyramidal motor symptoms and cognitive impairment. Inhaled manganese can bypass the blood-brain barrier and reach the central nervous system by transport down the olfactory nerve to the brain’s olfactory bulb. However, the mechanism by which Mn disrupts neural function remains unclear. Here we used optical imaging techniques to visualize exocytosis in olfactory nerve terminals in vivo in the mouse olfactory bulb. Acute Mn exposure via intranasal instillation of 2–200 μg MnCl2 solution caused a dose-dependent reduction in odorant-evoked neurotransmitter release, with significant effects at as little as 2 μg MnCl2 and a 90% reduction compared to vehicle controls with a 200 μg exposure. This reduction was also observed in response to direct electrical stimulation of the olfactory nerve layer in the olfactory bulb, demonstrating that Mn’s action is occurring centrally, not peripherally. This is the first direct evidence that Mn intoxication can disrupt neurotransmitter release, and is consistent with previous work suggesting that chronic Mn exposure limits amphetamine-induced dopamine increases in the basal ganglia despite normal levels of dopamine synthesis (Guilarte et al., J Neurochem 2008). The commonality of Mn’s action between glutamatergic neurons in the olfactory bulb and dopaminergic neurons in the basal ganglia suggests that a disruption of neurotransmitter release may be a general consequence wherever Mn accumulates in the brain and could underlie its pleiotropic effects.
PMCID: PMC3432160  PMID: 22542936
Manganese; Olfactory; Olfaction; Imaging; Pathophysiology; Exocytosis
12.  Progesterone Signaling Mechanisms in Brain and Behavior 
Steroid hormone, progesterone, modulates neuroendocrine functions in the central nervous system resulting in alterations in physiology and behavior. These neuronal effects are mediated primarily by intracellular progestin receptors (PRs) in the steroid-sensitive neurons, resulting in transcription-dependent genomic actions (classical mechanism). In addition to progesterone, intracellular PRs can also be activated in a “ligand-independent” manner by neurotransmitters, peptide growth factors, cyclic nucleotides, and neurosteroids. Recent studies indicate that rapid, non-classical progesterone actions involving cytoplasmic kinase signaling and/or extranuclear PRs can result in both transcription-independent and transcription-dependent actions. Cross-talk between extranuclear and classical intracellular signaling pathways promotes progesterone-dependent behavior in mammals. This review focuses on the mechanisms by which progesterone-initiated signaling mechanisms converge with PRs in the brain to modulate reproductive behavior in female rodents.
PMCID: PMC3355960  PMID: 22649404
progesterone; progestin receptors; dopamine; non-classical; signaling; cross-talk
13.  The Role of Neurotrophins in Neurotransmitter Release 
The neurotrophins (NTs) have recently been shown to elicit pronounced effects on quantal neurotransmitter release at both central and peripheral nervous system synapses. Due to their activity-dependent release, as well as the subcellular localization of both protein and receptor, NTs are ideally suited to modify the strength of neuronal connections by “fine-tuning” synaptic activity through direct actions at presynaptic terminals. Here, using BDNF as a prototypical example, the authors provide an update of recent evidence demonstrating that NTs enhance quantal neurotransmitter release at synapses through presynaptic mechanisms. The authors further propose that a potential target for NT actions at presynaptic terminals is the mechanism by which terminals retrieve synaptic vesicles after exocytosis. Depending on the temporal demands placed on synapses during high-frequency synaptic transmission, synapses may use two alternative modes of synaptic vesicle retrieval, the conventional slow endosomal recycling or a faster rapid retrieval at the active zone, referred to as “kiss-and-run.” By modulating Ca2+ microdomains associated with voltage-gated Ca2+ channels at active zones, NTs may elicit a switch from the slow to the fast mode of endocytosis of vesicles at presynaptic terminals during high-frequency synaptic transmission, allowing more reliable information transfer and neuronal signaling in the central nervous system.
PMCID: PMC2810653  PMID: 12467374
BDNF; Docked vesicles; Fusion pore; Hippocampus; mEPSC; Poisson stimulation; Quantal release; SNARE proteins; Synaptic vesicles; TrkB; Voltage-gated Ca2+ channels
14.  Role of the Adipocyte-derived Hormone Leptin in Reproductive Control 
Achievement of sexual maturation and maintenance of fertility in adulthood are functions sensitive to the metabolic status of the organism, particularly the magnitude of fat reserves. In this sense, the adipocyte-derived hormone, leptin, plays a major role linking metabolic cues and the control of multiple neuroendocrine axes. The hypothalamus is a key site mediating leptin actions, including those involved in the modulation of the hypothalamus-pituitary-gonads (HPG) axis at different stages of development and in different environmental conditions. In the present review, we intend to provide an update of the role of leptin in reproduction and to discuss its interactions with neurons, neurotransmitters and downstream targets of the reproductive axis, with a special emphasis on the actions of leptin in the central nervous system. We hope this review will contribute to the understanding of the mechanisms whereby metabolic signals, especially leptin, influence the reproductive neuroendocrine axis modulating its activity in different nutritional states. Special attention will be given to recent advances in the identification of key hypothalamic sites and signaling pathways relevant to leptin’s action in reproductive control.
PMCID: PMC4242683  PMID: 25390022
Hypothalamus; energy balance; leptin; GnRH; Kiss1; gonadotropins; fertility
15.  Selective vulnerability of cerebellar granule neuroblasts and their progeny to drugs with abuse liability 
Cerebellum (London, England)  2003;2(3):184-195.
Cerebellar development is shaped by the interplay of genetic and numerous environmental factors. Recent evidence suggests that cerebellar maturation is acutely sensitive to drugs with abuse liability including alcohol, opioids, and nicotine. Assuming substance abuse disrupts cerebellar maturation, a central question is to what are the basic mechanisms underlying potential drug-induced developmental defects. Evidence reviewed herein suggests that the maturation of granule neurons and their progeny are intrinsically affected by several classes of substances with abuse liability. Although drug abuse is also likely to target directly other cerebellar neuron and glial types, such as Purkinje cells and Bergmann glia, findings in isolated granule neurons suggest that they are often the principle target for drug actions. Developmental events that are selectively disrupted by drug abuse in granule neurons and/or their neuroblast precursors include proliferation, migration, differentiation (including neurite elaboration and synapse formation), and programmed cell death. Moreover, different classes of drugs act through distinct molecular mechanisms thereby disrupting unique aspects of development. For example, drug-induced perturbations in (i) neurotransmitter biogenesis, (ii) ligand and ion-gated receptor function and their coupling to intracellular effectors, (iii) neurotrophic factor biogenesis and signaling, and (iv) intercellular adhesion are all likely to have significant effects in shaping developmental outcome. In addition to identifying therapeutic strategies for drug abuse intervention, understanding the mechanisms by which drugs affect cellular maturation is likely to provide a better understanding of the neurochemical events that normally shape central nervous system development.
PMCID: PMC4306667  PMID: 14509568
neuroblast proliferation; cerebellar development; programmed cell death; nicotinic acetylcholinergic receptors; opioid receptors; heroin; nicotine
16.  Visualization of acetylcholine distribution in central nervous system tissue sections by tandem imaging mass spectrometry 
Analytical and Bioanalytical Chemistry  2012;403(7):1851-1861.
Metabolite distribution imaging via imaging mass spectrometry (IMS) is an increasingly utilized tool in the field of neurochemistry. As most previous IMS studies analyzed the relative abundances of larger metabolite species, it is important to expand its application to smaller molecules, such as neurotransmitters. This study aimed to develop an IMS application to visualize neurotransmitter distribution in central nervous system tissue sections. Here, we raise two technical problems that must be resolved to achieve neurotransmitter imaging: (1) the lower concentrations of bioactive molecules, compared with those of membrane lipids, require higher sensitivity and/or signal-to-noise (S/N) ratios in signal detection, and (2) the molecular turnover of the neurotransmitters is rapid; thus, tissue preparation procedures should be performed carefully to minimize postmortem changes. We first evaluated intrinsic sensitivity and matrix interference using Matrix Assisted Laser Desorption/Ionization (MALDI) mass spectrometry (MS) to detect six neurotransmitters and chose acetylcholine (ACh) as a model for study. Next, we examined both single MS imaging and MS/MS imaging for ACh and found that via an ion transition from m/z 146 to m/z 87 in MS/MS imaging, ACh could be visualized with a high S/N ratio. Furthermore, we found that in situ freezing method of brain samples improved IMS data quality in terms of the number of effective pixels and the image contrast (i.e., the sensitivity and dynamic range). Therefore, by addressing the aforementioned problems, we demonstrated the tissue distribution of ACh, the most suitable molecular specimen for positive ion detection by IMS, to reveal its localization in central nervous system tissues.
PMCID: PMC3358544  PMID: 22526660
Imaging mass spectrometry; Neurotransmitter; Acetylcholine; MS; MS/MS; Imaging; IMS
17.  Alcohol Induces Synaptotagmin 1 Expression in Neurons via Activation of Heat Shock Factor 1 
Neuroscience  2011;193:63-71.
Many synapses within the central nervous system are sensitive to ethanol. Although alcohol is known to affect the probability of neurotransmitter release in specific brain regions, the effects of alcohol on the underlying synaptic vesicle fusion machinery have been little studied. To identify a potential pathway by which ethanol can regulate neurotransmitter release, we investigated the effects of acute alcohol exposure (1–24 hours) on the expression of the gene encoding Synaptotagmin 1 (Syt1), a synaptic protein that binds calcium to directly trigger vesicle fusion. Syt1 was identified in a microarray screen as a gene that may be sensitive to alcohol and heat shock. We found that Syt1 mRNA and protein expression are rapidly and robustly up-regulated by ethanol in mouse cortical neurons, and that the distribution of Syt1 protein along neuronal processes is also altered. Syt1 mRNA up-regulation is dependent on the activation of the transcription factor heat shock factor 1 (HSF1). The transfection of a constitutively active Hsf1 construct into neurons stimulates Syt1 transcription, while transfection of Hsf1 siRNA or a constitutively inactive Hsf1 construct into neurons attenuates the induction of Syt1 by ethanol. This suggests that the activation of HSF1 can induce Syt1 expression and that this may be a mechanism by which alcohol regulates neurotransmitter release during brief exposures. Further analysis revealed that a subset of the genes encoding the core synaptic vesicle fusion (SNARE) proteins share this property of induction by ethanol, suggesting that alcohol may trigger a specific coordinated adaptation in synaptic function. This molecular mechanism could explain some of the changes in synaptic function that occur following alcohol administration, and may be an important step in the process of neuronal adaptation to alcohol.
PMCID: PMC3202342  PMID: 21816209
alcohol; synaptotagmin 1 (Syt1); heat shock factor 1 (HSF1); SNARE proteins; gene expression; cortical neurons
18.  Botulinum Neurotoxins A and E Undergo Retrograde Axonal Transport in Primary Motor Neurons 
PLoS Pathogens  2012;8(12):e1003087.
The striking differences between the clinical symptoms of tetanus and botulism have been ascribed to the different fate of the parental neurotoxins once internalised in motor neurons. Tetanus toxin (TeNT) is known to undergo transcytosis into inhibitory interneurons and block the release of inhibitory neurotransmitters in the spinal cord, causing a spastic paralysis. In contrast, botulinum neurotoxins (BoNTs) block acetylcholine release at the neuromuscular junction, therefore inducing a flaccid paralysis. Whilst overt experimental evidence supports the sorting of TeNT to the axonal retrograde transport pathway, recent findings challenge the established view that BoNT trafficking is restricted to the neuromuscular junction by highlighting central effects caused by these neurotoxins. These results suggest a more complex scenario whereby BoNTs also engage long-range trafficking mechanisms. However, the intracellular pathways underlying this process remain unclear. We sought to fill this gap by using primary motor neurons either in mass culture or differentiated in microfluidic devices to directly monitor the endocytosis and axonal transport of full length BoNT/A and BoNT/E and their recombinant binding fragments. We show that BoNT/A and BoNT/E are internalised by spinal cord motor neurons and undergo fast axonal retrograde transport. BoNT/A and BoNT/E are internalised in non-acidic axonal carriers that partially overlap with those containing TeNT, following a process that is largely independent of stimulated synaptic vesicle endo-exocytosis. Following intramuscular injection in vivo, BoNT/A and TeNT displayed central effects with a similar time course. Central actions paralleled the peripheral spastic paralysis for TeNT, but lagged behind the onset of flaccid paralysis for BoNT/A. These results suggest that the fast axonal retrograde transport compartment is composed of multifunctional trafficking organelles orchestrating the simultaneous transfer of diverse cargoes from nerve terminals to the soma, and represents a general gateway for the delivery of virulence factors and pathogens to the central nervous system.
Author Summary
Botulinum neurotoxins are the most toxic molecules known to mankind, and as a result, are currently listed among the top bio-threats. However, their ability to bind specifically to neurons and their inhibitory effects on regulated secretion prompted their clinical use in pathologies characterised by increased muscular tone, such as dystonia and various forms of spasticity, or abnormal secretion, such as drooling and excessive sweating, to cite a few. As a consequence, botulinum neurotoxin A, which is the serotype most commonly used in human therapy, has become the treatment of choice for an ever-expanding number of pathological and non-pathological (e.g. cosmetic) conditions. All current indications show that the systemic effects and toxicity of botulinum neurotoxin A are minimised by the specific route of administration (local injection) and the low diffusion of this molecule in tissues. However, recent reports suggest that in contrast to this common belief, botulinum neurotoxin A is able to reach distal sites in the body and may have previously unanticipated effects in the central nervous system. In this study, we demonstrate that botulinum neurotoxin A and E enter alternative endocytic pathway(s) in addition to synaptic vesicle recycling, and undergo long-range transport in a non degradative compartment in spinal cord motor neurons. Our results show that axonal retrograde transport is a common pathway for the dissemination in the central nervous system of pathogens and virulence factors important for human and animal health.
PMCID: PMC3531519  PMID: 23300443
19.  Intrinsic properties and neuropharmacology of midline paraventricular thalamic nucleus neurons 
Neurons in the midline and intralaminar thalamic nuclei are components of an interconnected brainstem, limbic and prefrontal cortex neural network that is engaged during arousal, vigilance, motivated and addictive behaviors, and stress. To better understand the cellular mechanisms underlying these functions, here we review some of the recently characterized electrophysiological and neuropharmacological properties of neurons in the paraventricular thalamic nucleus (PVT), derived from whole cell patch clamp recordings in acute rat brain slice preparations. PVT neurons display firing patterns and ionic conductances (IT and IH) that exhibit significant diurnal change. Their resting membrane potential (RMP) is maintained by various ionic conductances that include inward rectifier (Kir), hyperpolarization-activated nonselective cation (HCN) and TWIK-related acid sensitive (TASK) K+ channels. Firing patterns are regulated by high voltage-activated (HVA) and low voltage-activated (LVA) Ca2+ conductances. Moreover, transient receptor potential (TRP)-like nonselective cation channels together with Ca2+- and Na+-activated K+ conductances (KCa; KNa) contribute to unique slow afterhyperpolarizing potentials (sAHPs) that are generally not detectable in lateral thalamic or reticular thalamic nucleus neurons. The excitability of PVT neurons is also modulated by activation of neurotransmitter receptors associated with afferent pathways to PVT and other thalamic midline nuclei. We report on receptor-mediated actions of GABA, glutamate, monoamines and several neuropeptides: arginine vasopressin, gastrin-releasing peptide, thyrotropin releasing hormone and the orexins (hypocretins). This review represents an initial survey of intrinsic and transmitter-sensitive ionic conductances that are deemed to be unique to this population of midline thalamic neurons, information that is fundamental to an appreciation of the role these thalamic neurons may play in normal central nervous system (CNS) physiology and in CNS disorders that involve the dorsomedial thalamus.
PMCID: PMC4029024  PMID: 24860449
midline thalamic nuclei; electrophysiology; peptides; diurnal and seasonal changes; burst firing
20.  Position of UNC-13 in the active zone regulates synaptic vesicle release probability and release kinetics 
eLife  2013;2:e01180.
The presynaptic active zone proteins UNC-13/Munc13s are essential for synaptic vesicle (SV) exocytosis by directly interacting with SV fusion apparatus. An open question is how their association with active zones, hence their position to Ca2+ entry sites, regulates SV release. The N-termini of major UNC-13/Munc13 isoforms contain a non-calcium binding C2A domain that mediates protein homo- or hetero-meric interactions. Here, we show that the C2A domain of Caenorhabditis elegans UNC-13 regulates release probability of evoked release and its precise active zone localization. Kinetics analysis of SV release supports that the proximity of UNC-13 to Ca2+ entry sites, mediated by the C2A-domain containing N-terminus, is critical for accelerating neurotransmitter release. Additionally, the C2A domain is specifically required for spontaneous release. These data reveal multiple roles of UNC-13 C2A domain, and suggest that spontaneous release and the fast phase of evoked release may involve a common pool of SVs at the active zone.
eLife digest
Neurons are connected to each other by junctions called synapses. When an electrical signal travelling along a neuron arrives at a synapse, it causes the release of bubble-like structures called synaptic vesicles that contain chemicals called neurotransmitters. When released by the vesicles these neurotransmitters bind to receptors on a second neuron and allow the signal to continue on its way through the nervous system.
The release of synaptic vesicles from the neuron depends largely on the number of calcium ions that enter this neuron via structures called ion channels, and also on the rate at which they enter. Vesicles are released in one of three ways: they can be released quickly (within a few milliseconds) in response to the influx of calcium ions; they can be released slowly (over a period of tens or hundreds of milliseconds) in response to the influx; or they can be released at random times that are not related to the influx.
It is known that the sensitivity of certain calcium sensors near the synapse influences the release of the vesicles. It had been thought that the distance between the “active zone” where the calcium ions enter the neuron and the region where the vesicles reside might also influence rate of release, but the molecular mechanism underlying this hypothesis is poorly understood.
Zhou et al. have now shed new light on this question by performing a series of experiments that involved manipulating a protein called UNC-13 – which is known to be involved in the release of vesicles – in neurons from C. elegans, a nematode worm. First it was shown that the precise position of UNC-13 in the active zone depended on a domain within the protein called the C2A domain. Next it was shown that the distance between the UNC-13 protein and the calcium ion channels strongly influences the quick mode of vesicle release. Finally, Zhou et al. showed that the C2A domain also had a significant influence on the spontaneous release of vesicles, which suggests that a common fleet of vesicles might be used for both the quick and the spontaneous modes of vesicle release. Zhou et al. also generated mutant worms that mimicked a neurological disease, epileptic seizure, and showed that eliminating the C2A domain can relieve some of the symptoms associated with the disease.
Many neurological diseases are caused by signals not being transmitted properly at synapses, so in addition to providing insights into the basic mechanism underlying synaptic action, these results could also assist with the development of new strategies for managing neurological diseases.
PMCID: PMC3821175  PMID: 24220508
UNC-13; Munc-13; SV release probability; SV release kinetics; C2A domain; miniSOG; Chromophore assisted light inactivation; C. elegans
21.  Serotonin Signaling in Schistosoma mansoni: A Serotonin–Activated G Protein-Coupled Receptor Controls Parasite Movement 
PLoS Pathogens  2014;10(1):e1003878.
Serotonin is an important neuroactive substance in all the parasitic helminths. In Schistosoma mansoni, serotonin is strongly myoexcitatory; it potentiates contraction of the body wall muscles and stimulates motor activity. This is considered to be a critical mechanism of motor control in the parasite, but the mode of action of serotonin is poorly understood. Here we provide the first molecular evidence of a functional serotonin receptor (Sm5HTR) in S. mansoni. The schistosome receptor belongs to the G protein-coupled receptor (GPCR) superfamily and is distantly related to serotonergic type 7 (5HT7) receptors from other species. Functional expression studies in transfected HEK 293 cells showed that Sm5HTR is a specific serotonin receptor and it signals through an increase in intracellular cAMP, consistent with a 5HT7 signaling mechanism. Immunolocalization studies with a specific anti-Sm5HTR antibody revealed that the receptor is abundantly distributed in the worm's nervous system, including the cerebral ganglia and main nerve cords of the central nervous system and the peripheral innervation of the body wall muscles and tegument. RNA interference (RNAi) was performed both in schistosomulae and adult worms to test whether the receptor is required for parasite motility. The RNAi-suppressed adults and larvae were markedly hypoactive compared to the corresponding controls and they were also resistant to exogenous serotonin treatment. These results show that Sm5HTR is at least one of the receptors responsible for the motor effects of serotonin in S. mansoni. The fact that Sm5HTR is expressed in nerve tissue further suggests that serotonin stimulates movement via this receptor by modulating neuronal output to the musculature. Together, the evidence identifies Sm5HTR as an important neuronal protein and a key component of the motor control apparatus in S. mansoni.
Author Summary
The bloodfluke Schistosoma mansoni causes human schistosomiasis, a debilitating disease that afflicts over 200 million people worldwide. There is no vaccine for schistosomiasis, and chemotherapy relies heavily on a single drug, praziquantel. With only one drug available, the prospect of drug resistance is a serious concern, particularly when praziquantel usage is on the rise due to mass treatment programs in many parts of the world. There is a pressing need to identify new drug targets and to develop new chemotherapeutics for schistosomiasis. The focus of this research is on the nervous system of S. mansoni. Many pesticides and antiparasitic drugs act by interacting with neuronal proteins and therefore the nervous system holds great promise for drug discovery. Here we describe a new protein that is present in the nervous system of S. mansoni and regulates movement of the worm. The protein was further identified as a specific receptor for serotonin, an important neurotransmitter and a known modulator of motility in schistosomes. This work shows that the serotonin receptor of S. mansoni is required for proper motor control and therefore is a potential target for chemotherapeutic intervention.
PMCID: PMC3894222  PMID: 24453972
22.  Fast retrieval and autonomous regulation of single spontaneously recycling synaptic vesicles 
eLife  null;3:e03658.
Presynaptic terminals release neurotransmitters spontaneously in a manner that can be regulated by Ca2+. However, the mechanisms underlying this regulation are poorly understood because the inherent stochasticity and low probability of spontaneous fusion events has curtailed their visualization at individual release sites. Here, using pH-sensitive optical probes targeted to synaptic vesicles, we visualized single spontaneous fusion events and found that they are retrieved extremely rapidly with faster re-acidification kinetics than their action potential-evoked counterparts. These fusion events were coupled to postsynaptic NMDA receptor-driven Ca2+ signals, and at elevated Ca2+ concentrations there was an increase in the number of vesicles that would undergo fusion. Furthermore, spontaneous vesicle fusion propensity in a synapse was Ca2+-dependent but regulated autonomously: independent of evoked fusion probability at the same synapse. Taken together, these results expand classical quantal analysis to incorporate endocytic and exocytic phases of single fusion events and uncover autonomous regulation of spontaneous fusion.
eLife digest
Neurons communicate with one another at junctions called synapses. When an electrical signal known as an action potential arrives at a synapse, it causes packages called vesicles to fuse with the membrane that surrounds the neuron. The vesicles contain molecules called neurotransmitters, which are then released into the gap between the neurons. When these molecules bind to receptors on the surface of the second neuron, a copy of the action potential is generated and travels along the second neuron. The empty vesicles are then reabsorbed back into the first cell to be refilled with neurotransmitters so that the whole process can be repeated.
In addition to releasing neurotransmitters in response to the arrival of an action potential, neurons sometimes release vesicles spontaneously. Such events are relatively rare and occur seemingly at random, making them difficult to study. However, by labeling a synaptic vesicle protein with a fluorescent protein, Leitz and Kavalali have constructed a system in which they can observe spontaneous vesicle fusions in single synapses in cell cultures, and follow the fate of the vesicles as they are reabsorbed back into the cell.
The results reveal a number of key differences between the spontaneous events and those triggered by action potentials. Vesicles released spontaneously are retrieved and recycled much more rapidly than those that are released following the arrival of an action potential. Moreover, increases in calcium levels increase the frequency of both types of events. However, it is also clear that the calcium ions influence the two types of events independently of one another.
Recent research on flies has suggested that some regions of synapses only ever release vesicles spontaneously, whereas others only ever release vesicles in response to the arrival of an action potential. The work of Leitz and Kavalali now adds to increasing evidence that the spontaneous release of neurotransmitters may have its own role in neuronal signaling that is distinct from the role played by neurotransmitters that are released in response to action potentials.
PMCID: PMC4270043  PMID: 25415052
synaptic vesicle recycling; synaptic terminals; spontaneous neurotransmitter release; Mouse; rat
23.  Targeting inhibitory neurotransmission in tinnitus 
Brain research  2012;1485:77-87.
Tinnitus perception depends on the presence of its neural correlates within the auditory neuraxis and associated structures. Targeting specific circuits and receptors within the central nervous system in an effort to relieve the perception of tinnitus and its impact on one’s emotional and mental state has become a focus of tinnitus research. One approach is to upregulate endogenous inhibitory neurotransmitter levels (e.g. glycine and GABA) and selectively target inhibitory receptors in key circuits to normalize tinnitus pathophysiology. Thus, the basic functional and molecular properties of two major ligand-gated inhibitory receptor systems, the GABAA receptor (GABAAR) and glycine receptor (GlyR) are described. Also reviewed is the rationale for targeting inhibition which stems from reported tinnitus-related homeostatic plasticity of inhibitory neurotransmitter systems and associated enhanced neuronal excitability throughout most central auditory structures. However, the putative role of the medial geniculate body (MGB) in tinnitus has not been previously addressed, specifically in terms of its inhibitory afferents from inferior colliculus and thalamic reticular nucleus and its GABAAR functional heterogeneity. This heterogeneous population of GABAARs, which may be altered in tinnitus pathology, and its key anatomical position in the auditory CNS make the MGB a compelling structure for tinnitus research. Finally, some selective compounds, which enhance tonic inhibition, have successfully ameliorated tinnitus in animal studies, suggesting that the MGB and, to a lesser degree, the auditory cortex may be their primary locus of action. These pharmacological interventions are examined, in terms of their mechanism of action and why these agents, may be effective in tinnitus treatment.
PMCID: PMC3374875  PMID: 22405692
tinnitus; GABAAR; GlyR; inhibition; medial geniculate body; homeostatic plasticity
24.  A Gain-of-function Mutation in Adenylate Cyclase Confers Isoflurane Resistance in C. elegans 
Anesthesiology  2011;115(6):1162-1171.
Volatile general anesthetics inhibit neurotransmitter release by a mechanism not fully understood. Genetic evidence in C. elegans has shown that a major mechanism of action of volatile anesthetics acting at clinical concentrations in this animal is presynaptic inhibition of neurotransmission. To define additional components of this presynaptic volatile anesthetic mechanism, C. elegans mutants isolated as phenotypic suppressors of a mutation in syntaxin, an essential component of the neurotransmitter release machinery, were screened for anesthetic sensitivity phenotypes.
Sensitivity to isoflurane concentrations was measured in locomotion assays on adult C. elegans. Sensitivity to the acetylcholinesterase inhibitor aldicarb was used as an assay for the global level of C. elegans acetylcholine release. Comparisons of isoflurane sensitivity (measured by the EC50) were made by simultaneous curve-fitting and F-test.
Among the syntaxin suppressor mutants, js127 was the most isoflurane resistant with an EC50 more than three-fold wild type. Genetic mapping, sequencing, and transformation phenocopy showed that js127 was an allele of acy-1, which encodes an adenylate cyclase expressed throughout the C. elegans nervous system and in muscle. js127 behaved as a gain-of-function mutation in acy-1 and had increased levels of cyclic adenosine monophosphate. Testing of single and double mutants along with selective tissue expression of the js127 mutation revealed that acy-1 acts in neurons within a G□s – PKA – UNC-13-dependent pathway to regulate behaviour and isoflurane sensitivity.
Activation of neuronal adenylate cyclase antagonizes isoflurane inhibition of locomotion in C. elegans.
PMCID: PMC3226976  PMID: 22024713
25.  Regulation of monoamine transporters: Influence of psychostimulants and therapeutic antidepressants 
The AAPS Journal  2005;7(3):E728-E738.
Synaptic neurotransmission in the central nervous system (CNS) requires the precise control of the duration and the magnitude of neurotransmitter action at specific 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 affinity 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 deficit 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 trafficking linked to cellular protein kinases, protein phosphatases, and transporter interacting proteins. The review also discusses the possible role of psychostimulants and antidepressants in influencing monoamine transport regulation.
PMCID: PMC2751275  PMID: 16353949
phosphorylation; trafficking; interacting proteins; substrates; and ligands

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