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Cells Feb 2020The cation channel subunit TRPC1 is strongly expressed in central neurons including neurons in the CA1 region of the hippocampus where it forms complexes with TRPC4 and...
The cation channel subunit TRPC1 is strongly expressed in central neurons including neurons in the CA1 region of the hippocampus where it forms complexes with TRPC4 and TRPC5. To investigate the functional role of TRPC1 in these neurons and in channel function, we compared current responses to group I metabotropic glutamate receptor (mGluR I) activation and looked for major differences in dendritic morphology in neurons from and mice. mGluR I stimulation resulted in the activation of a voltage-dependent nonselective cation current in both genotypes. Deletion of TRPC1 resulted in a modification of the shape of the current-voltage relationship, leading to an inward current increase. In current clamp recordings, the percentage of neurons that responded to depolarization in the presence of an mGluR I agonist with a plateau potential was increased in mice. There was also a small increase in the minor population of CA1 neurons that have more than one apical dendrite in mice. We conclude that TRPC1 has an inhibitory effect on receptor-operated nonselective cation channels in hippocampal CA1 neurons probably as a result of heterotetramer formation with other TRPC isoforms, and that TRPC1 deletion has only minor effects on dendritic morphology.
Topics: Animals; CA1 Region, Hippocampal; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Receptors, Metabotropic Glutamate; TRPC Cation Channels
PubMed: 32085504
DOI: 10.3390/cells9020459 -
CNS Neuroscience & Therapeutics Feb 2024To investigate the role of mGluR1α in cerebellar unipolar brush cells (UBC) in mediating vestibular compensation (VC), using mGluR1α agonist and antagonist to modulate...
AIMS
To investigate the role of mGluR1α in cerebellar unipolar brush cells (UBC) in mediating vestibular compensation (VC), using mGluR1α agonist and antagonist to modulate ON UBC neurons, and explore the mGluR1/IP3/extracellular signal-regulated kinase (ERK) signaling pathway.
METHODS
First, AAV virus that knockdown ON UBC (mGluR1α) were injected into cerebellar UBC by stereotactic, and verified by immunofluorescence and western blot. The effect on VC was evaluated after unilateral labyrinthectomy (UL). Second, saline, (RS)-3,5-dihydroxyphenylglycine (DHPG), and LY367385 were injected into tubes implanted in rats at different time points after UL separately. The effect on ON UBC neuron activity was evaluated by immunofluorescence. Then, Phosphoinositide (PI) and p-ERK1/2 levels of mGluR1α were analyzed by ELISA after UL. The protein levels of p-ERK and total ERK were verified by western blot. In addition, the effect of mGluR1α activation or inhibition on VC-related behavior was observed.
RESULTS
mGluR1α knockdown induced VC phenotypes. DHPG increased ON UBC activity, while LY367385 reduced ON UBC activity. DHPG group showed an increase in PI and p-ERK1/2 levels, while LY367385 group showed a decrease in PI and p-ERK1/2 levels in cerebellar UBC of rats. The western blot results of p-ERK and total ERK confirm and support the observations. DHPG alleviated VC-related behavior phenotypes, while LY367385 exacerbated vestibular decompensation-like behavior induced by UL.
CONCLUSION
mGluR1α activity in cerebellar ON UBC is crucial for mediating VC through the mGluR1/IP3/ERK signaling pathway, which affects ON UBC neuron activity and contributes to the pathogenesis of VC.
Topics: Rats; Animals; Extracellular Signal-Regulated MAP Kinases; Signal Transduction; Benzoates; Glycine; Methoxyhydroxyphenylglycol; Receptors, Metabotropic Glutamate
PubMed: 37622292
DOI: 10.1111/cns.14419 -
BMC Research Notes Apr 2018Norepinephrine (NE), a sympathetic neurotransmitter, is often measured in plasma as an index of sympathetic activity. To better understand NE dynamics, it is important...
OBJECTIVE
Norepinephrine (NE), a sympathetic neurotransmitter, is often measured in plasma as an index of sympathetic activity. To better understand NE dynamics, it is important to measure its principal metabolite, 3,4-dihydroxyphenylglycol (DHPG), concurrently. Our aim was to present a method, developed in the course of a translational research study, to measure NE and DHPG in human plasma using high performance liquid chromatography with electrochemical detection (HPLC-ED).
RESULTS
After pre-purifying plasma samples by alumina extraction, we used HPLC-ED to separate and quantify NE and DHPG. In order to remove uric acid, which co-eluted with DHPG, a sodium bicarbonate wash was added to the alumina extraction procedure, and we oxidized the column eluates followed by reduction because catechols are reversibly oxidized whereas uric acid is irreversibly oxidized. Average recoveries of plasma NE and DHPG were 35.3 ± 1.0% and 16.3 ± 1.1%, respectively, and there was no detectable uric acid. Our estimated detection limits for NE and DHPG were approximately 85 pg/mL (0.5 pmol/mL) and 165 pg/mL (0.9 pmol/mL), respectively. The measurement of NE and DHPG in human plasma has wide applicability; thus, we describe a method to quantify plasma NE and DHPG in a laboratory setting as a useful tool for translational and clinical research.
Topics: Chromatography, High Pressure Liquid; Electrochemical Techniques; Heart Failure; Humans; Methoxyhydroxyphenylglycol; Norepinephrine; Sympathetic Nervous System; Translational Research, Biomedical
PubMed: 29673396
DOI: 10.1186/s13104-018-3352-3 -
Movement Disorders : Official Journal... Sep 2008Patients with Parkinson's disease (PD) often have manifestations of autonomic failure. About 40% have neurogenic orthostatic hypotension (NOH), and among PD+NOH patients...
Patients with Parkinson's disease (PD) often have manifestations of autonomic failure. About 40% have neurogenic orthostatic hypotension (NOH), and among PD+NOH patients virtually all have evidence of cardiac sympathetic denervation; however, whether PD+NOH entails extra-cardiac noradrenergic denervation has been less clear. Microdialysate concentrations of the main neuronal metabolite of norepinephrine (NE) and dihydroxyphenylglycol (DHPG) were measured in skeletal muscle, and plasma concentrations of NE and DHPG were measured in response to i.v. tyramine, yohimbine, and isoproterenol, in patients with PD+NOH, patients with pure autonomic failure (PAF), which is characterized by generalized catecholaminergic denervation, and control subjects. Microdialysate DHPG concentrations were similarly low in PD+NOH and PAF compared to control subjects (163 +/- 25, 153 +/- 27, and 304 +/- 27 pg/mL, P < 0.01 each vs. control). The two groups also had similarly small plasma DHPG responses to tyramine (71 +/- 58 and 82 +/- 105 vs. 313 +/- 94 pg/mL; P < 0.01 each vs. control) and NE responses to yohimbine (223 +/- 37 and 61 +/- 15 vs. 672 +/- 130 pg/mL, P < 0.01 each vs. control), and virtually absent NE responses to isoproterenol (20 +/- 34 and 14 +/- 15 vs. 336 +/- 78 pg/mL, P < 0.01 each vs. control). Patients with PD+NOH had normal bradycardia responses to edrophonium and normal epinephrine responses to glucagon. The results support the concept of generalized noradrenergic denervation in PD+NOH, with similar severity to that seen in PAF. In contrast, the parasympathetic cholinergic and adrenomedullary hormonal components of the autonomic nervous system seem intact in PD+NOH.
Topics: Aged; Blood Pressure; Bradycardia; Cholinesterase Inhibitors; Edrophonium; Epinephrine; Female; Glucagon; Humans; Hypotension, Orthostatic; Isoproterenol; Male; Methoxyhydroxyphenylglycol; Microdialysis; Middle Aged; Muscle, Skeletal; Norepinephrine; Parkinson Disease; Pure Autonomic Failure; Tyramine; Yohimbine
PubMed: 18661549
DOI: 10.1002/mds.22226 -
Cell Reports Nov 2021A core network of widely expressed proteins within the glutamatergic post-synapse mediates activity-dependent synaptic plasticity throughout the brain, but the specific...
A core network of widely expressed proteins within the glutamatergic post-synapse mediates activity-dependent synaptic plasticity throughout the brain, but the specific proteomic composition of synapses differs between brain regions. Here, we address the question, how does proteomic composition affect activity-dependent protein-protein interaction networks (PINs) downstream of synaptic activity? Using quantitative multiplex co-immunoprecipitation, we compare the PIN response of in vivo or ex vivo neurons derived from different brain regions to activation by different agonists or different forms of eyeblink conditioning. We report that PINs discriminate between incoming stimuli using differential kinetics of overlapping and non-overlapping PIN parameters. Further, these "molecular logic rules" differ by brain region. We conclude that although the PIN of the glutamatergic post-synapse is expressed widely throughout the brain, its activity-dependent dynamics show remarkable stimulus-specific and brain-region-specific diversity. This diversity may help explain the challenges in developing molecule-specific drug therapies for neurological disorders.
Topics: Animals; Blinking; Brain; Conditioning, Eyelid; Excitatory Amino Acid Agonists; Female; Male; Methoxyhydroxyphenylglycol; Mice; N-Methylaspartate; Neuronal Plasticity; Protein Interaction Maps; Proteome; Synapses
PubMed: 34852231
DOI: 10.1016/j.celrep.2021.110076 -
Neuropharmacology Jan 2018mGlu5 receptors are involved in mechanisms of activity-dependent synaptic plasticity, and are targeted by drugs developed for the treatment of CNS disorders. We report...
mGlu5 receptors are involved in mechanisms of activity-dependent synaptic plasticity, and are targeted by drugs developed for the treatment of CNS disorders. We report that mGlu3 receptors, which are traditionally linked to the control of neurotransmitter release, support mGlu5 receptor signaling in neurons and largely contribute to the robust mGlu5 receptor-mediated polyphosphoinositide hydrolysis in the early postnatal life. In cortical pyramidal neurons, mGlu3 receptor activation potentiated mGlu5 receptor-mediated somatic Ca mobilization, and mGlu3 receptor-mediated long-term depression in the prefrontal cortex required the endogenous activation of mGlu5 receptors. The interaction between mGlu3 and mGlu5 receptors was also relevant to mechanisms of neuronal toxicity, with mGlu3 receptors shaping the influence of mGlu5 receptors on excitotoxic neuronal death. These findings shed new light into the complex role played by mGlu receptors in physiology and pathology, and suggest reconsideration of some of the current dogmas in the mGlu receptor field.
Topics: Amino Acids; Animals; Animals, Newborn; Astrocytes; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Central Nervous System; Embryo, Mammalian; Excitatory Amino Acid Agents; Female; Gene Expression Regulation, Developmental; Humans; Hydrolysis; Long-Term Potentiation; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; N-Methylaspartate; Neurons; Phosphatidylinositol Phosphates; Rats; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate
PubMed: 29079293
DOI: 10.1016/j.neuropharm.2017.10.026 -
The Journal of Physiology Jan 2017The midbrain periaqueductal grey (PAG) forms part of an endogenous analgesic system which is tightly regulated by the neurotransmitter GABA. The role of endocannabinoids...
KEY POINTS
The midbrain periaqueductal grey (PAG) forms part of an endogenous analgesic system which is tightly regulated by the neurotransmitter GABA. The role of endocannabinoids in regulating GABAergic control of this system was examined in rat PAG slices. Under basal conditions GABAergic neurotransmission onto PAG output neurons was multivesicular. Activation of the endocannabinoid system reduced GABAergic inhibition by reducing the probability of release and by shifting release to a univesicular mode. Blockade of endocannabinoid system unmasked a tonic control over the probability and mode of GABA release. These findings provides a mechanistic foundation for the control of the PAG analgesic system by disinhibition.
ABSTRACT
The midbrain periaqueductal grey (PAG) has a crucial role in coordinating endogenous analgesic responses to physiological and psychological stressors. Endocannabinoids are thought to mediate a form of stress-induced analgesia within the PAG by relieving GABAergic inhibition of output neurons, a process known as disinhibition. This disinhibition is thought to be achieved by a presynaptic reduction in GABA release probability. We examined whether other mechanisms have a role in endocannabinoid modulation of GABAergic synaptic transmission within the rat PAG. The group I mGluR agonist DHPG ((R,S)-3,5-dihydroxyphenylglycine) inhibited evoked IPSCs and increased their paired pulse ratio in normal external Ca , and when release probability was reduced by lowering Ca . However, the effect of DHPG on the coefficient of variation and kinetics of evoked IPSCs differed between normal and low Ca . Lowering external Ca had a similar effect on evoked IPSCs to that observed for DHPG in normal external Ca . The low affinity GABA receptor antagonist TPMPA ((1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid) inhibited evoked IPSCs to a greater extent in low than in normal Ca . Together these findings indicate that the normal mode of GABA release is multivesicular within the PAG, and that DHPG and lowering external Ca switch this to a univesicular mode. The effects of DHPG were mediated by mGlu5 receptor engagement of the retrograde endocannabinoid system. Blockade of endocannabinoid breakdown produced a similar shift in the mode of release. We conclude that endocannabinoids control both the mode and the probability of GABA release within the PAG.
Topics: Animals; Calcium; Endocannabinoids; Female; GABA Antagonists; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Methoxyhydroxyphenylglycol; Periaqueductal Gray; Phosphinic Acids; Piperidines; Pyrazoles; Pyridines; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Synapses; gamma-Aminobutyric Acid
PubMed: 27461371
DOI: 10.1113/JP272292 -
Clinical Autonomic Research : Official... Aug 2013Autonomic neuropathy is widely recognized to be associated with upper gastrointestinal symptoms and abnormal (i.e., rapid or slow) gastric emptying. While patients with...
PURPOSE
Autonomic neuropathy is widely recognized to be associated with upper gastrointestinal symptoms and abnormal (i.e., rapid or slow) gastric emptying. While patients with postural orthostatic tachycardia syndrome (POTS) may also have gastrointestinal symptoms, our understanding of gastric-emptying disturbances in POTS is very limited. The objectives of this study were to evaluate the relationship between gastric-emptying disturbances and gastrointestinal symptoms in patients with POTS.
METHODS
We retrospectively reviewed the medical records of 22 well-characterized patients with POTS and upper gastrointestinal symptoms in whom autonomic (i.e., postganglionic sudomotor, cardiovagal, and adrenergic) functions and gastric emptying were evaluated using standardized techniques and scintigraphy, respectively. Medical records were reviewed retrospectively to assess clinical features, gastric emptying, and autonomic functions.
RESULTS
Over 70 % of patients had nausea and/or vomiting, which was the most common GI symptom; other common symptoms were abdominal pain (59 %), bloating (55 %), and postprandial fullness/early satiety (46 %). Over one-third of patients had abnormal [i.e., rapid (27 %) or delayed (9 %)] gastric emptying. Gastric-emptying disturbances were not significantly associated with GI symptoms, autonomic symptoms or autonomic dysfunction.
CONCLUSIONS
Over one-third of patients with POTS and gastrointestinal symptoms have abnormal, more frequently rapid than delayed gastric emptying. These findings need to be confirmed in a larger cohort of patients.
Topics: Adolescent; Adult; Autonomic Nervous System; Female; Gastric Emptying; Gastrointestinal Diseases; Gastrointestinal Motility; Gastroparesis; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Postural Orthostatic Tachycardia Syndrome; Radionuclide Imaging; Radiopharmaceuticals; Retrospective Studies; Stomach; Surveys and Questionnaires; Technetium Tc 99m Sulfur Colloid; Young Adult
PubMed: 23708963
DOI: 10.1007/s10286-013-0193-y -
Journal of Integrative Neuroscience Jun 2022There has been increasing evidence that exercise therapy is effective in the treatment and prevention of major depression (MD). However, the basic molecular mechanisms...
The Molecular Mechanism of Exercise for Treatment of Patients with Major Depression: A Preliminary Report on the Dynamics of Metabolites of Nitric Oxide and Catecholamines.
BACKGROUND
There has been increasing evidence that exercise therapy is effective in the treatment and prevention of major depression (MD). However, the basic molecular mechanisms underlying the effects of exercise on MD remain unclear. We conducted a preliminary study to clarify the effect of exercise therapy on MD, focusing on the dynamics of nitric oxide (NO) and catecholamine metabolites, which have been found to be associated with MD.
METHODS
Eleven outpatients with mild to moderate MD and 37 healthy controls (HC) were included in the study. The participants' clinical records and questionnaires were screened for their past medical history. For their exercise therapy, the participants were instructed to walk the equivalent of 17.5 kcal/kg/week for 8 weeks. Blood samples were collected from all participants at baseline, 4 weeks, and 8 weeks after the start of exercise therapy, and plasma metabolites of NO (NOx), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were analyzed. We also assessed the 17-item Hamilton Rating Scale for Depression (HRSD-17) in patients with MD. A mixed-effects regression model was used to compare the mean values by time (baseline, 4, and 8 weeks) for the three corresponding groups (NOx, MHPG, and HVA).
RESULTS
HRSD-17 scores decreased significantly in the MD group after 8 weeks of exercise therapy. NOx and MHPG increased, but there was no significant change in HVA in the MD group after the exercise therapy. NOx decreased after exercise, and HVA increased significantly from baseline after 4 weeks of exercise but decreased after 8 weeks of exercise in the HC group.
CONCLUSIONS
The effects of exercise on NOx, MHPG, and HVA may differ between MD and HC. The potential mechanisms for the benefits of walking exercise in MD patients will be the subject for future research.
Topics: Catecholamines; Depression; Depressive Disorder, Major; Homovanillic Acid; Humans; Methoxyhydroxyphenylglycol; Nitric Oxide
PubMed: 35864774
DOI: 10.31083/j.jin2104123 -
Nature Neuroscience Oct 2011Oligodendrocyte precursor cells (OPCs), a major glial cell type that gives rise to myelinating oligodendrocytes in the CNS, express calcium-permeable AMPA receptors...
Oligodendrocyte precursor cells (OPCs), a major glial cell type that gives rise to myelinating oligodendrocytes in the CNS, express calcium-permeable AMPA receptors (CP-AMPARs). Although CP-AMPARs are important for OPC proliferation and neuron-glia signaling, they render OPCs susceptible to ischemic damage in early development. We identified factors controlling the dynamic regulation of AMPAR subtypes in OPCs from rat optic nerve and mouse cerebellar cortex. We found that activation of group 1 mGluRs drove an increase in the proportion of CP-AMPARs, reflected by an increase in single-channel conductance and inward rectification. This plasticity required the elevation of intracellular calcium and used PI3K, PICK-1 and the JNK pathway. In white matter, neurons and astrocytes release both ATP and glutamate. Unexpectedly, activation of purinergic receptors in OPCs decreased CP-AMPAR expression, suggesting a capacity for homeostatic regulation. Finally, we found that stargazin-related transmembrane AMPAR regulatory proteins, which are critical for AMPAR surface expression in neurons, regulate CP-AMPAR plasticity in OPCs.
Topics: Animals; Animals, Newborn; Antigens; Biophysical Phenomena; Calcium; Calcium Channels; Carrier Proteins; Cell Cycle Proteins; Cell Differentiation; Cell Lineage; Cerebellum; Enzyme Inhibitors; Excitatory Amino Acid Agents; Female; Galactosylceramidase; Gene Expression Regulation, Developmental; Glutamic Acid; Glycine Agents; In Vitro Techniques; Ion Channel Gating; Luminescent Proteins; Male; Membrane Potentials; Methoxyhydroxyphenylglycol; Mice; Mice, Transgenic; Mutation; Neuronal Plasticity; Nuclear Proteins; Oligodendroglia; Optic Nerve; Proteoglycans; Rats; Receptors, AMPA; Signal Transduction; Stem Cells; Strychnine; Tetrodotoxin
PubMed: 21983683
DOI: 10.1038/nn.2942