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Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Epileptic encephalopathies associated with chorea:28GNAO1 mutations.SCN1A-related phenotypic.FOXG1 mutations.SCN8A mutations.SCN2A-related disorders.UBA5 mutations.DNM1 mutations.FRRS1L mutations.GRIN1/GRIN2B/GRIN2D mutations.
Cognition Enhancers
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Ramneek Kaur, Rashi Rajput, Sachin Kumar, Harleen Kaur, R. Rachana, Manisha Singh
The role of glycine and D-serine as a co-agonist was determined more than 25 years ago (Johnson and Ascher, 1987; Kleckner and Dingledine, 1988). These amino acids bind to GluN1 component of the NMDA receptor and glutamate (the classic agonist) binds to GluN2 subunit. Simultaneous binding of these subunits, that is, GluN1 and GluN2 causes the full activation of NMDA receptor (Laube et al., 1997). There is a release of glutamate from the synaptic bouton during the synaptic transmission and it is anticipated that the obtainability of glutamate extracellular spaces regulates the functioning of the receptor and thereby, affecting the synaptic plasticity. It is applicable for both D-serine (Yang et al., 2003) and glycine (Martina et al., 2004). With aging, the concentrations of D-serine and serine racemase (an enzyme that forms D-serine from L-serine) decrease in hippocampus region (Turpin et al., 2011). This shortcoming can be amended by the addition of D-serine, which helps in restoring the plasticity in hippocampus from mouse model suffering from SAMP8 (senescence accelerated mouse-prone 8) and aged rats (Yang et al., 2005). Further, an addition of D-serine up-regulates the neurogenesis in vitro and in vivo (Sultan et al., 2013).
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
The ionotropic glutamate receptors are ion channels for sodium, potassium, and calcium similar to the nicotinic ACh receptor. These ligand-gated channels are opened by glutamate as well as various synthetic chemicals with a similar structure leading to excitation (depolarization) of the neuron on which they are found. Three subtypes of ionotropic glutamate receptors have been identified based on the chemicals that were highly effective in activating them: 1) N-methyl-D-aspartate or NMDA receptor, 2) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid or AMPA receptor, and 3) kainic acid or kainate receptor. In the past, these receptors were separated into NMDA and non-NMDA because of the antagonists that blocked either the NMDA or non-NMDA (AMPA, kainate) receptors. Another difference between NMDA and non-NMDA receptors is their selectivity for ion conductance with NMDA channels able to conduct sodium and calcium and non-NMDA (AMPA, kainate) that typically depolarize the cell with a sodium current. Just as the nicotinic ACh and GABA receptors were composed of several protein subunits that form the ion channel, the EAA receptors are also composed of subunits. However, unlike the nicotinic ACh, GABA and glycine receptors, which were composed of five subunits (i.e., pentamers), the ionotropic glutamate receptors are composed of four protein subunits (i.e., tetramers). A variety of protein subunits that comprise the EAA receptors have been identified through molecular cloning. The subunits for the NMDA receptor are referred to as GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3B, and those for the AMPA receptor are designated as GluA1–GluA4. The protein subunits that form the kainate receptor include GluK1–GluK5.168 The subunit composition of an NMDA or non-NMDA receptor may differ in different regions of the brain.
Dyskinesia and Parkinson’s disease: animal model, drug targets, and agents in preclinical testing
Published in Expert Opinion on Therapeutic Targets, 2022
Valentina Cesaroni, Fabio Blandini, Silvia Cerri
Glutamate is the most representative excitatory neurotransmitter of the central nervous system and there are extensive preclinical and clinical evidence suggesting changes in thalamo-cortical-striatal glutamatergic transmission and altered expression of both ionotropic and metabotropic receptors involved in LID development. Ionotropic glutamate receptors are ligand-gated ion channels involved in fast excitatory transmission in the central nervous system which are generally named according to their specific ligands: kainate, α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), and NMDA. NMDA receptors are formed by a tetrameric complex of different subunits (GluN1, GluN2, GluN3 or NR1, NR2, NR3), responsible for its biophysical and pharmacological properties. The observation of an increased activation of striatal NMDA receptors in experimental models of dyskinesia and in the brain of PD patients with LID [34,53] have suggested the use of antagonists and modulators of these receptors as potential anti-dyskinetic strategy. Similarly, preclinical studies on animal models of LID have reported a modification in the phosphorylation state of the AMPA receptors and their massive synaptic involvement in the striatum, proposing them to be a possible drug targets for ameliorating this side effect (see Table 2).
Aconiti lateralis Radix Praeparata inhibits Alzheimer’s disease by regulating the complex regulation network with the core of GRIN1 and MAPK1
Published in Pharmaceutical Biology, 2021
Yutao Wang, Huixiang Zhang, Jing Wang, Ming Yu, Qianqian Zhang, Shan Yan, Dingyun You, Lanlan Shi, Lihuan Zhang, Limei Wang, Hongxiang Wu, Xue Cao
For another, GRIN1 and MAPK1 have been closely related to neurodegeneration, synaptic plasticity, cell survival and AD in previous researches (Coyle et al. 2016; Preciados et al. 2016; Sun and Nan 2017; Lu and Malemud 2019). GRIN1 protein is a critical subunit of NMDA (Kaniakova et al. 2012), which is the target of memantine (Robinson and Keating 2006), and plays a key role in memory and learning by regulating the plasticity of synapses (Mori et al. 2011; Wang et al. 2011). GluN1 receptors and GRIN1 gene expression levels and location are significantly different in AD samples compared to controls (Leuba et al. 2014; Mohamed et al. 2015; Agca et al. 2020). The MAPK1 gene is believed as one age-dependent transcriptional changing gene that involves in the abnormal hyperphosphorylation of the tau-protein, causing aggregated neurofibrillary tangles (Kálmán et al. 2009). Moreover, galantamine could treat Alzheimer’s disease by attenuating the activation of MAPK1 (Noda et al. 2010). Taken these results together, we hypothesise that the complex regulation network with the core of GRIN1 and MAPK1 may play a key role in the process of Fuzi anti-AD.
Oligomeric Aβ25–35 induces the tyrosine phosphorylation of PSD-95 by SrcPTKs in rat hippocampal CA1 subfield
Published in International Journal of Neuroscience, 2023
Gui-Mei Wu, Cai-Ping Du, Yan Xu
In the hippocampus, NMDA receptors are composed mainly of GluN1 subunits in combination with GluN2A or GluN2B subunits [24, 32]. We examined the effects of selective antagonists of GluN2A and GluN2B subunits (NVP-AAM077 and Ro25-6981) on tyrosine phosphorylation of PSD-95 in rat hippocampal CA1 subfield. NVP-AAM077 or Ro25-6981 was administered 20 min before Aβ25–35 injection. As shown in Figure 4, both NVP-AAM077 and Ro25-6981 attenuated the tyrosine phosphorylation of PSD-95 significantly at 3 days after Aβ25–35 injection (Figure 4A and B). The protein level of PSD-95 was not altered (Figure 4A and B). These findings suggest that both GluN2A and GluN2B-containing NMDA receptors mediate the tyrosine phosphorylation of PSD-95 induced by Aβ25–35 oligomers.