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G protein-coupled receptor kinases as regulators of dopamine receptor functions.
Gurevich EV, Gainetdinov RR, Gurevich VV
(2016) Pharmacol Res 111: 1-16
MeSH Terms: Animals, Basal Ganglia, Central Nervous System Stimulants, G-Protein-Coupled Receptor Kinases, Humans, Parkinsonian Disorders, Phosphorylation, Receptors, Dopamine, Signal Transduction
Show Abstract · Added March 14, 2018
Actions of the neurotransmitter dopamine in the brain are mediated by dopamine receptors that belong to the superfamily of G protein-coupled receptors (GPCRs). Mammals have five dopamine receptor subtypes, D1 through D5. D1 and D5 couple to Gs/olf and activate adenylyl cyclase, whereas D2, D3, and D4 couple to Gi/o and inhibit it. Most GPCRs upon activation by an agonist are phosphorylated by GPCR kinases (GRKs). The GRK phosphorylation makes receptors high-affinity binding partners for arrestin proteins. Arrestin binding to active phosphorylated receptors stops further G protein activation and promotes receptor internalization, recycling or degradation, thereby regulating their signaling and trafficking. Four non- visual GRKs are expressed in striatal neurons. Here we describe known effects of individual GRKs on dopamine receptors in cell culture and in the two in vivo models of dopamine-mediated signaling: behavioral response to psychostimulants and L-DOPA- induced dyskinesia. Dyskinesia, associated with dopamine super-sensitivity of striatal neurons, is a debilitating side effect of L-DOPA therapy in Parkinson's disease. In vivo, GRK subtypes show greater receptor specificity than in vitro or in cultured cells. Overexpression, knockdown, and knockout of individual GRKs, particularly GRK2 and GRK6, have differential effects on signaling of dopamine receptor subtypes in the brain. Furthermore, deletion of GRK isoforms in select striatal neuronal types differentially affects psychostimulant-induced behaviors. In addition, anti-dyskinetic effect of GRK3 does not require its kinase activity: it is mediated by the binding of its RGS-like domain to Gαq/11, which suppresses Gq/11 signaling. The data demonstrate that the dopamine signaling in defined neuronal types in vivo is regulated by specific and finely orchestrated actions of GRK isoforms.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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9 MeSH Terms
Phase-amplitude coupling, an indication of bursting in parkinsonism, is masked by periodic pulses.
Sanders TH
(2016) J Neurophysiol 115: 1587-95
MeSH Terms: Animals, Brain Waves, Macaca mulatta, Male, Mice, Mice, Inbred C57BL, Models, Neurological, Neurons, Parkinsonian Disorders, Thalamic Nuclei
Show Abstract · Added August 8, 2017
Interactions between neural oscillations in the brain have been observed in many structures including the hippocampus, amygdala, motor cortex, and basal ganglia. In this study, one popular approach for quantifying oscillation interactions was considered: phase-amplitude coupling. The goals of the study were to use simulations to examine potential causes of elevated phase-amplitude coupling in parkinsonism, to compare simulated parkinsonian signals with recorded local field potentials from animal models of parkinsonism, to investigate possible relationships between increased bursting in parkinsonian single cells and elevated phase-amplitude coupling, and to uncover potential noise and artifact effects. First, a cell model that integrates incremental input currents and fires at realistic voltage thresholds was modified to allow control of stochastic parameters related to firing and burst rates. Next, the input currents and distribution of integration times were set to reproduce firing patterns consistent with those from parkinsonian subthalamic nucleus cells. Then, local field potentials were synthesized from the output of multiple simulated cells with varying degrees of synchronization and compared with subthalamic nucleus recordings from animal models of parkinsonism. The results showed that phase-amplitude coupling can provide important information about underlying neural activity. In particular, signals synthesized from synchronized bursting neurons showed increased oscillatory interactions similar to those observed in parkinsonian animals. Additionally, changes in bursting parameters such as the intraburst rate, the mean interburst period, and the amount of synchronization between neurons influenced the phase-amplitude coupling in predictable ways. Finally, simulation results revealed that small periodic signals can have a surprisingly large masking effect on phase-amplitude coupling.
Copyright © 2016 the American Physiological Society.
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10 MeSH Terms
M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia.
Shen W, Plotkin JL, Francardo V, Ko WK, Xie Z, Li Q, Fieblinger T, Wess J, Neubig RR, Lindsley CW, Conn PJ, Greengard P, Bezard E, Cenci MA, Surmeier DJ
(2015) Neuron 88: 762-73
MeSH Terms: Allosteric Regulation, Animals, Cerebral Cortex, Disease Models, Animal, Dopamine Agents, Dyskinesia, Drug-Induced, Glutamic Acid, Levodopa, Long-Term Potentiation, Long-Term Synaptic Depression, Macaca mulatta, Mice, Mice, Transgenic, Neostriatum, Neuronal Plasticity, Neurons, Parkinsonian Disorders, RGS Proteins, Receptor, Muscarinic M4, Signal Transduction
Show Abstract · Added February 18, 2016
A balanced interaction between dopaminergic and cholinergic signaling in the striatum is critical to goal-directed behavior. But how this interaction modulates corticostriatal synaptic plasticity underlying learned actions remains unclear--particularly in direct-pathway spiny projection neurons (dSPNs). Our studies show that in dSPNs, endogenous cholinergic signaling through M4 muscarinic receptors (M4Rs) promoted long-term depression of corticostriatal glutamatergic synapses, by suppressing regulator of G protein signaling type 4 (RGS4) activity, and blocked D1 dopamine receptor dependent long-term potentiation (LTP). Furthermore, in a mouse model of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease (PD), boosting M4R signaling with positive allosteric modulator (PAM) blocked aberrant LTP in dSPNs, enabled LTP reversal, and attenuated dyskinetic behaviors. An M4R PAM also was effective in a primate LID model. Taken together, these studies identify an important signaling pathway controlling striatal synaptic plasticity and point to a novel pharmacological strategy for alleviating LID in PD patients.
Copyright © 2015 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features.
Kwakye GF, Paoliello MM, Mukhopadhyay S, Bowman AB, Aschner M
(2015) Int J Environ Res Public Health 12: 7519-40
MeSH Terms: Brain, Dopamine, Glutamic Acid, Humans, Magnesium, Manganese Poisoning, Parkinson Disease, Parkinsonian Disorders, gamma-Aminobutyric Acid
Show Abstract · Added February 15, 2016
Manganese (Mn) is an essential trace element necessary for physiological processes that support development, growth and neuronal function. Secondary to elevated exposure or decreased excretion, Mn accumulates in the basal ganglia region of the brain and may cause a parkinsonian-like syndrome, referred to as manganism. The present review discusses the advances made in understanding the essentiality and neurotoxicity of Mn. We review occupational Mn-induced parkinsonism and the dynamic modes of Mn transport in biological systems, as well as the detection and pharmacokinetic modeling of Mn trafficking. In addition, we review some of the shared similarities, pathologic and clinical distinctions between Mn-induced parkinsonism and Parkinson's disease. Where possible, we review the influence of Mn toxicity on dopamine, gamma aminobutyric acid (GABA), and glutamate neurotransmitter levels and function. We conclude with a survey of the preventive and treatment strategies for manganism and idiopathic Parkinson's disease (PD).
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9 MeSH Terms
Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson's disease and L-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist.
Iderberg H, Maslava N, Thompson AD, Bubser M, Niswender CM, Hopkins CR, Lindsley CW, Conn PJ, Jones CK, Cenci MA
(2015) Neuropharmacology 95: 121-9
MeSH Terms: Aminobutyrates, Animals, Antiparkinson Agents, Catalepsy, Dyskinesia, Drug-Induced, Excitatory Amino Acid Agents, Haloperidol, Levodopa, Male, Oxidopamine, Parkinsonian Disorders, Phosphinic Acids, Picolinic Acids, Random Allocation, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate
Show Abstract · Added February 18, 2016
Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the 'indirect pathway' of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of haloperidol-induced catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic treatment with full doses of l-DOPA. When given together with l-DOPA to rats with already established dyskinesias, neither VU0364770 nor LSP1-2111 modified the abnormal involuntary movement scores. VU0364770 potentiated, however, the motor stimulant effect of a subthreshold l-DOPA dose in certain behavioural tests, whereas LSP1-2111 lacked this ability. Taken together, these results indicate that a pharmacological stimulation of mGlu4 lacks intrinsic antidyskinetic activity, but may have DOPA-sparing activity in Parkinson's disease. For the latter indication, mGlu4 PAMs appear to provide a better option than orthosteric agonists.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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16 MeSH Terms
SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity.
Leyva-Illades D, Chen P, Zogzas CE, Hutchens S, Mercado JM, Swaim CD, Morrisett RA, Bowman AB, Aschner M, Mukhopadhyay S
(2014) J Neurosci 34: 14079-95
MeSH Terms: Animals, Caenorhabditis elegans, Cation Transport Proteins, Cell Membrane, Cells, Cultured, Female, HeLa Cells, Humans, Intracellular Fluid, Male, Manganese, Mice, Inbred C57BL, Mutation, Parkinsonian Disorders, Protein Transport, Zinc Transporter 8
Show Abstract · Added February 3, 2015
Manganese (Mn) is an essential metal, but elevated cellular levels are toxic and may lead to the development of an irreversible parkinsonian-like syndrome that has no treatment. Mn-induced parkinsonism generally occurs as a result of exposure to elevated Mn levels in occupational or environmental settings. Additionally, patients with compromised liver function attributable to diseases, such as cirrhosis, fail to excrete Mn and may develop Mn-induced parkinsonism in the absence of exposure to elevated Mn. Recently, a new form of familial parkinsonism was reported to occur as a result of mutations in SLC30A10. The cellular function of SLC30A10 and the mechanisms by which mutations in this protein cause parkinsonism are unclear. Here, using a combination of mechanistic and functional studies in cell culture, Caenorhabditis elegans, and primary midbrain neurons, we show that SLC30A10 is a cell surface-localized Mn efflux transporter that reduces cellular Mn levels and protects against Mn-induced toxicity. Importantly, mutations in SLC30A10 that cause familial parkinsonism blocked the ability of the transporter to traffic to the cell surface and to mediate Mn efflux. Although expression of disease-causing SLC30A10 mutations were not deleterious by themselves, neurons and worms expressing these mutants exhibited enhanced sensitivity to Mn toxicity. Our results provide novel insights into the mechanisms involved in the onset of a familial form of parkinsonism and highlight the possibility of using enhanced Mn efflux as a therapeutic strategy for the potential management of Mn-induced parkinsonism, including that occurring as a result of mutations in SLC30A10.
Copyright © 2014 the authors 0270-6474/14/3414079-17$15.00/0.
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16 MeSH Terms
Missense dopamine transporter mutations associate with adult parkinsonism and ADHD.
Hansen FH, Skjørringe T, Yasmeen S, Arends NV, Sahai MA, Erreger K, Andreassen TF, Holy M, Hamilton PJ, Neergheen V, Karlsborg M, Newman AH, Pope S, Heales SJ, Friberg L, Law I, Pinborg LH, Sitte HH, Loland C, Shi L, Weinstein H, Galli A, Hjermind LE, Møller LB, Gether U
(2014) J Clin Invest 124: 3107-20
MeSH Terms: Adult, Amino Acid Sequence, Amino Acid Substitution, Animals, Attention Deficit Disorder with Hyperactivity, Brain, Cohort Studies, DNA Mutational Analysis, Dopamine, Dopamine Plasma Membrane Transport Proteins, Female, HEK293 Cells, Humans, Male, Models, Molecular, Molecular Sequence Data, Mutant Proteins, Mutation, Missense, Oocytes, Parkinsonian Disorders, Pedigree, Positron-Emission Tomography, Protein Conformation, Recombinant Proteins, Sequence Homology, Amino Acid, Sodium, Tomography, Emission-Computed, Single-Photon, Xenopus
Show Abstract · Added February 19, 2015
Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.
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28 MeSH Terms
Parkinsonism-related features of neuronal discharge in primates.
Sanders TH, Clements MA, Wichmann T
(2013) J Neurophysiol 110: 720-31
MeSH Terms: Animals, Data Interpretation, Statistical, Globus Pallidus, Macaca mulatta, Neurons, Parkinsonian Disorders, Subthalamic Nucleus
Show Abstract · Added August 8, 2017
Parkinson's disease is known to be associated with abnormal electrical spiking activities of basal ganglia neurons, including changes in firing rate, bursting activities and oscillatory firing patterns and changes in entropy. We explored the relative importance of these measures through optimal feature selection and discrimination analysis methods. We identified key characteristics of basal ganglia activity that predicted whether the neurons were recorded in the normal or parkinsonian state. Starting with 29 features extracted from the spike timing of neurons recorded in normal and parkinsonian monkeys in the internal or external segment of the globus pallidus or the subthalamic nucleus (STN), we used a method that incorporates a support vector machine algorithm to find feature combinations that optimally discriminate between the normal and parkinsonian states. Our results demonstrate that the discrimination power of combinations of specific features is higher than that of single features, or of all features combined, and that the most discriminative feature sets differ substantially between basal ganglia structures. Each nucleus or class of neurons in the basal ganglia may react differently to the parkinsonian condition, and the features used to describe this state should be adapted to the neuron type under study. The feature that was overall most predictive of the parkinsonian state in our data set was a high STN intraburst frequency. Interestingly, this feature was not correlated with parameters describing oscillatory firing properties in recordings made in the normal condition but was significantly correlated with spectral power in specific frequency bands in recordings from the parkinsonian state (specifically with power in the 8-13 Hz band).
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7 MeSH Terms
Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by mitochondrion-targeted cytochrome P450 2D6: implications in Parkinson disease.
Bajpai P, Sangar MC, Singh S, Tang W, Bansal S, Chowdhury G, Cheng Q, Fang JK, Martin MV, Guengerich FP, Avadhani NG
(2013) J Biol Chem 288: 4436-51
MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Adrenergic alpha-Antagonists, Animals, Cell Line, Cytochrome P-450 CYP2D6, Dopamine Agents, Dopaminergic Neurons, Dynamins, Humans, Mice, Mitochondria, Mitochondrial Proteins, Parkinsonian Disorders, Quinidine, Reactive Oxygen Species, Ubiquitin-Protein Ligases
Show Abstract · Added March 26, 2014
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic side product formed in the chemical synthesis of desmethylprodine opioid analgesic, which induces Parkinson disease. Monoamine oxidase B, present in the mitochondrial outer membrane of glial cells, catalyzes the oxidation of MPTP to the toxic 1-methyl-4-phenylpyridinium ion (MPP(+)), which then targets the dopaminergic neurons causing neuronal death. Here, we demonstrate that mitochondrion-targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the metabolism of MPTP to MPP(+), as shown with purified enzymes and also in cells expressing mitochondrial CYP2D6. Neuro-2A cells stably expressing predominantly mitochondrion-targeted CYP2D6 were more sensitive to MPTP-mediated mitochondrial respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Mitochondrial CYP2D6 expressing Neuro-2A cells produced higher levels of reactive oxygen species and showed abnormal mitochondrial structures. MPTP treatment also induced mitochondrial translocation of an autophagic marker, Parkin, and a mitochondrial fission marker, Drp1, in differentiated neurons expressing mitochondrial CYP2D6. MPTP-mediated toxicity in primary dopaminergic neurons was attenuated by CYP2D6 inhibitor, quinidine, and also partly by monoamine oxidase B inhibitors deprenyl and pargyline. These studies show for the first time that dopaminergic neurons expressing mitochondrial CYP2D6 are fully capable of activating the pro-neurotoxin MPTP and inducing neuronal damage, which is effectively prevented by the CYP2D6 inhibitor quinidine.
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16 MeSH Terms
Cognitive effects of dopamine depletion in the context of diminished acetylcholine signaling capacity in mice.
Zurkovsky L, Bychkov E, Tsakem EL, Siedlecki C, Blakely RD, Gurevich EV
(2013) Dis Model Mech 6: 171-83
MeSH Terms: Acetylcholine, Animals, Cholinergic Agents, Cognition Disorders, Dementia, Disease Models, Animal, Dopamine, Hemicholinium 3, Humans, Male, Membrane Transport Proteins, Memory, Mice, Mice, Inbred C57BL, Mice, Knockout, Parkinsonian Disorders, Signal Transduction
Show Abstract · Added July 10, 2013
A subset of patients with Parkinson's disease acquires a debilitating dementia characterized by severe cognitive impairments (i.e. Parkinson's disease dementia; PDD). Brains from PDD patients show extensive cholinergic loss as well as dopamine (DA) depletion. We used a mutant mouse model to directly test whether combined cholinergic and DA depletion leads to a cognitive profile resembling PDD. Mice carrying heterozygous deletion of the high-affinity, hemicholinium-3-sensitive choline transporter (CHT(HET)) show reduced levels of acetylcholine throughout the brain. We achieved bilateral DA depletion in CHT(HET) and wild-type (WT) littermates via intra-striatal infusion of 6-hydroxydopamine (6-OHDA), or used vehicle as control. Executive function and memory were evaluated using rodent versions of cognitive tasks commonly used with human subjects: the set-shifting task and spatial and novel-object recognition paradigms. Our studies revealed impaired acquisition of attentional set in the set-shifting paradigm in WT-6OHDA and CHT(HET)-vehicle mice that was exacerbated in the CHT(HET)-6OHDA mice. The object recognition test following a 24-hour delay was also impaired in CHT(HET)-6OHDA mice compared with all other groups. Treatment with acetylcholinesterase (AChE) inhibitors physostigmine (0.05 or 0.1 mg/kg) and donepezil (0.1 and 0.3 mg/kg) reversed the impaired object recognition of the CHT(HET)-6OHDA mice. Our data demonstrate an exacerbated cognitive phenotype with dual ACh and DA depletion as compared with either insult alone, with traits analogous to those observed in PDD patients. The results suggest that combined loss of DA and ACh could be sufficient for pathogenesis of specific cognitive deficits in PDD.
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17 MeSH Terms