Glutamate receptor activation

Dingledine R, et al. Glutamate receptor ion channels. Pharmacol Rev. Rothstein JD, et al. Localization of neuronal and glial glutamate transporters.

Glutamate transporters bring competition to the synapse. Curr Opin Neurobiol. Nowak L, et al. Magnesium gates glutamate-activated channels in mouse central neurones. Seeburg PH, et al. Recent Prog Hormone Res. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path.

J Physiol. Trends Neurosci. Synaptic plasticity at thalamocortical synapses in developing rat somatosensory cortex: LTP, LTD, and silent synapses. J Neurobiol. Johnston D. Neurochem Int. Kapur A, et al. L-Type calcium channels are required for one form of hippocampal mossy fiber LTP. J Neurophysiol. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade.

Isaac J. Protein phosphatase 1 and LTD: synapses are the architects of depression. Spruston N, et al. Activity-dependent action potential invasion and calcium infiux into hippocampal CA1 dendrites. Stuart G, et al.

Action potential initiation and backpropagation in neurons of the mammalian CNS. Markram H, et al. Long-term synaptic plasticity between pairs of individual CA3 pyramidal cells in rat hippocampal slice cultures. Asynchronous pre- and post-synaptic activity induces associative long-term depression in area CA1 of the rat hippocampus in vitro. Synaptic plasticity: taming the beast. Nat Neurosci. Kepecs A, et al. Spike-timing-dependent plasticity: common themes and divergent vistas.

Biol Cybernet. Lisman J, Spruston N. Dan Y, Poo MM. Spike timing-dependent plasticity: from synapse to perception. Physiol Rev. Extending the effects of spike-timing-dependent plasticity to behavioral timescales. Lin YW, et al. Spike-timing-dependent plasticity at resting and conditioned lateral perforant path synapses on granule cells in the dentate gyrus: different roles of N-methyl-D-aspartate and group I metabotropic glutamate receptors.

Eur J Neurosci. Gerkin RC, et al. Bi G, et al. Annu Rev Neurosci. Stable Hebbian learning from spike timing-dependent plasticity. J Neurosci. Schiller J, et al. NMDA spikes in basal dendrites of cortical pyramidal neurons. Schiller J, Schiller Y. NMDAR-mediated dendritic spikes and coincident signal amplification.

Enoki R, et al. Neurosci Res. Plasticity compartments in basal dendrites of neocortical pyramidal neurons. Nevian T, et al. Properties of basal dendrites of layer 5 pyramidal neurons: a direct patch-clamp recording study. London M, Hausser M. Dendritic computation. Rhodes P. The properties and implications of NMDA spikes in neocortical pyramidal cells. Gasparini S, Magee JC.

State-dependent dendritic computation in hippocam-pal CA1 pyramidal neurons. Lisman J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory.

Brickley SG, et al. Hardingham GE, Bading H. Vanhoutte P, Bading H. Liu L, et al. Massey PV, et al. Berberich S, et al. Morishita W, et al. Husi H, Grant SG. Proteomics of the nervous system. Husi H, et al. Kennedy MB. Signal-processing machines at the postsynaptic density. Brambilla R, et al. A role for the Ras signalling pathway in synaptic transmission and long-term memory.

Gnegy ME. Crit Rev Neurobiol. Sheng M. J Cell Sci. Sweatt JD. The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem. Riccio A, Ginty DD. Deisseroth K, et al. Signaling from synapse to nucleus: the logic behind the mechanisms. Johnson JW, Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Kleckner NW, Dingledine R.

Adv Exp Med Biol. Panatier A, et al. Ascher P. D-cycloserine: a ligand for the N-methyl-D-aspartate coupled glycine receptor has partial agonist characteristics. Neurosci Lett. Competitive antagonists and partial agonists at the glycine modulatory site of the mouse N-methyl-D-aspartate receptor. Brain Res. Anticonvulsant activity of antagonists and partial agonists for the NMDAR-associated glycine site in the kindling model of epilepsy. Seguin L, Millan MJ. Tricklebank MD, et al. The anticonvulsant and behavioural profile of L,, a partial agonist acting at the glycine modulatory site on the N-methyl-D-aspartate NMDA receptor complex.

Brit J Pharmacol. Pussinen R, et al. Enhancement of intermediate-term memory by an alpha-1 agonist or a partial agonist at the glycine site of the NMDAR. Neurobiol Learn Mem. Priestley T, et al. L,, a low efficacy NMDAR glycine site partial agonist in vitro , does not prevent hippocampal LTP in vivo at plasma levels known to be neuroprotective.

Ballard TM, et al. Severe impairment of NMDAR function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity. Ann NY Acad Sci. The neuropsychopharmacology of phencyclidine: from NMDAR hypofunction to the dopamine hypothesis of schizophrenia.

Coyle JT, Tsai G. NMDAR function, neuroplasticity, and the pathophysiology of schizophrenia. Int Rev Neurobiol. Pilowsky LS, et al.

Mol Psych. Neher E, Sakmann B. Single-channel currents recorded from membrane of denervated frog muscle fibres. NMDAR pharmacology and analysis of patch-clamp recordings. Meth Mol Biol. The polyamine spermine has multiple actions on N-methyl-D-aspartate receptor single-channel currents in cultured cortical neurons. Mol Pharmacol. Single-channel and whole-cell analysis of ethanol inhibition of NMDA-activated currents in cultured mouse cortical and hippocampal neurons.

Gibb AJ, Colquhoun D. Popescu G, et al. Erreger K, et al. Glutamate activates multiple single channel conductances in hippocampal neurons.

Stern P, et al. Wyllie DJ, et al. Structural conservation of ion conduction pathways in K channels and glutamate receptors. Activation-dependent subconductance levels in K channels suggest a subunit basis for ion permeation and gating. Biophys J. K channel subconductance levels result from heteromeric pore conformations.

J Gen Physiol. VanDongen AMJ. Structure and function of ion channels: a hole in four? Comm Theor Biol. VanDongen AM. K channel gating by an affinity-switching selectivity filter. Baker KA, et al. Conformational dynamics of the KcsA potassium channel governs gating properties. Rare Cancers of Childhood Treatment. Childhood Cancer Genomics.

Study Findings. Metastatic Cancer Research. Intramural Research. Extramural Research. Cancer Research Workforce. Partners in Cancer Research. What Are Cancer Research Studies. Research Studies. Get Involved. Cancer Biology Research. Cancer Genomics Research. Research on Causes of Cancer. Cancer Prevention Research.

Cancer Treatment Research. Cancer Health Disparities. Childhood Cancers Research. Global Cancer Research. Cancer Research Infrastructure. Clinical Trials.

Frederick National Laboratory for Cancer Research. Bioinformatics, Big Data, and Cancer. Annual Report to the Nation. Research Advances by Cancer Type. Stories of Discovery. Milestones in Cancer Research and Discovery. Biomedical Citizen Science. Director's Message. Budget Proposal. Stories of Cancer Research. Driving Discovery. Pharmacological NMDAR blockade in the monocrotaline rat model of pulmonary hypertension had beneficial effects on cardiac and vascular remodeling, decreasing endothelial dysfunction, cell proliferation, and apoptosis resistance while disrupting the glutamate-NMDAR pathway in pulmonary arteries.

Keywords: NMDA receptor; endothelin-1; glutamate; platelet-derived growth factor; pulmonary arterial hypertension; smooth muscle cell; vascular remodeling.

D Mutation study to identify the coordination residues. The EC 50 value of the mutant was 4. The representative confocal images are shown. Next, we performed a functional characterization of the newly identified EC mutant. The EC 50 value of glutamate to induce activation of the EC mutant was 4. We also assessed the distribution and expression level of the EC mutant under live-cell conditions.

As shown in Figure 2H , confocal live imaging of HEK cells transfected with either the WT mGlu1 or the EC mutant revealed the clear localization of the probe on the cell surface, while the fluorescent signal was hardly detectable in vector-transfected cells. In metal-binding proteins, the coordination geometry has essential roles for the function or metal-selectivity. As a result, this mutant cannot be applied for orthogonal activation in conjunction with the Pd bpy -responsive mutant.

A Heat map of the secondary screening. See Supplementary Figure S5 for raw data. Lower ; representative traces of the cells from two mutants. The black bar shows the period when ZnCl 2 was added. The EC 50 value for the mutant was 0. The EC 50 value of the mutant was 0. To verify whether the original ligand-binding property of mGlu1 is preserved in this mutant, the dose-dependent glutamate response was also measured. As shown in Figure 3D , the EC 50 value of glutamate for the activation of this mutant was 0.

In addition, confocal live imaging using FITM-Cy3 revealed that the distribution and the expression level of the mGlu1 mutant were not affected by the introduction of these mutations Figures 3E,F. Besides, the metal-induced activations were repeatedly observed after washing out the bound metals for 2 min, suggesting a minutes-order reversibility of the activation Supplementary Figure S7.

Considering these properties of the three mutants, we demonstrated cell-specific mGlu1 activation. In this experiment, we regarded each of these transfected cells as different cell types. After 48 h of transfection, these three types of HEK cells were mixed and seeded on a single glass coverslip Figure 4A. Notably, the glutamate-induced responses were intact after metal-induced activation, suggesting that mGlu1 activity was not affected after metal-induced activation.

The black bars inside the figure show the period when each reagent was added. The white arrows show the representative cells marked in A. In this study, three mutually orthogonal mutants for the dA-CBC system were developed. This system was termed as the oA-CBC system. Although our current study was limited to demonstrating this orthogonal activation in HEK cells, the oA-CBC system has the potential to analyze mGlu1 function in several different human brain regions simultaneously using tissue-selective promoters in the brain, given that mGlu1 is expressed in the olfactory bulb, thalamus, hippocampus, and cerebellum in the brain Lavreysen et al.

The mGlu family comprises eight subtypes mGlu1—8 and is classified into three groups group I—III based on the amino-acid sequence and transducing signal properties of each subtype Niswender and Conn, Although both are predominantly expressed in the brain, their distribution is different.

Unlike mGlu1, mGlu5 is expressed in the caudate-putamen, lateral septum, and cortex in the brain Romano et al. Although both subtypes are expressed in the hippocampus, previous studies revealed that the functional contributions of each subtype are different in the region Neyman and Manahan-Vaughan, Group I metabotropic glutamate receptor agonists such as 3,5-dihydroxyphenylglycine DHPG are frequently used to analyze the physiological roles of these receptors Fitzjohn et al.

However, this agonist cannot discriminate mGlu1 from mGlu5 because of the high sequence homology. Thus, it is challenging to independently activate and analyze mGlu1 or mGlu5 expressed in the same region of the brain. Therefore, potential future work could be to apply the oA-CBC method to mGlu5, thus creating an orthogonal pair of mGlu1 and mGlu5 mutants.

The mutants could be activated by two different metal ions or complexes and utilized for the subtype-selective activation of mGlu proteins. Another future application of our oA-CBC method is to construct an artificial signal-transducing system using three different metal ions or complexes as its input.

The oA-CBC method can also be applied to other types of mGlu proteins to artificially hijack different types of G-protein signals in an orthogonal way. SK and IH conceived the study.