Novel Treatment of Excitotoxicity: Targeted Disruption of Intracellular Signalling From Glutamate Receptors
Novel Treatment of Excitotoxicity: Targeted Disruption of Intracellular Signalling From Glutamate Receptors
NH2 C-CH2一CH2CH HO OH Glutamate (glutamic acid) Ending Glial Cell Glutamate Gluatamate Glutamate ● Nerve Cell
Glutamate
Excitotoxicity Presynaptic terminal NMDA-R Glutamate O Nitric Oxide Synthase 6的 Mitochondrial damage Proteases Phospholipases Postsynaptic neuron K Na NMDA-R
Excitotoxicity
Glutamate receptor and excitotoxicity Types of Glutamate receptor Glutamate Receptors lonotropic NMDA AMPA Kainate Metabotropic groupI group Il NR3 Kainate group III PCP.MK801 SAP102 (GlUR6KA2) Homer 3(mGluR15 5in-1800
Glutamate receptor and excitotoxicity Types of Glutamate receptor
Neurotransmitter binds lons flow mGluRs membrane G-protein- opens modulate ion channels G-protein-coupled membrane receptors Downregulate K+channel and upregulate non-selection cation channel Inhibit GABA receptor activity and potentiate iGluR function Mediate neuronal plasticity,nociception,pain and neurodegeneretion
mGluRs ❖ G-protein-coupled membrane receptors ❖ Downregulate K+ channel and upregulate non-selection cation channel ❖ Inhibit GABA receptor activity and potentiate iGluR function ❖ Mediate neuronal plasticity, nociception, pain and neurodegeneretion
iGluRs 刷远简 APA Na"ca" lon Currents Intracellular Domain Ligand-gated ion channels,permeable to Na',K+or Ca2t Mediate synaptic plasticity related to much of the toxicity induced by glutamate
iGluRs Ligand-gated ion channels, permeable to Na+ , K+ or Ca2+ Mediate synaptic plasticity related to much of the toxicity induced by glutamate
Ligand Binding Domai AMPA receptors Editing Structure of GluR2 Permeable to Na+.K+ Also permeable to Ca2+unless it contain GluR2 Loss of GluR2 implicated in delayed death of neurones in ischemia
AMPA receptors Permeable to Na+, K+ Also permeable to Ca2+ unless it contain GluR2 Loss of GluR2 implicated in delayed death of neurones in ischemia Structure of GluR2
Firure L.Kaul.M Liptos 8A NMDA-Rc NOS Ca NMDA receptors 15 ROS NO Caspases ef 2C APOPTOSIS Highly permeableto Ca2+and Na Calcium transients responsible for the physiologic effects of NMDAR signalling Calcium transientsalso trigger excitotoxic death
NMDA receptors Highly permeable to Ca2+ and Na+ Calcium transients responsible for the physiologic effects of NMDAR signalling Calcium transients also trigger excitotoxic death
Kainate receptors Share many of the same structural characteristics as NMDA and AMPA receptors Until recently,little was known about the functional and physiological roles of kainate receptors in the mammalian CNS
Kainate receptors Share many of the same structural characteristics as NMDA and AMPA receptors Until recently, little was known about the functional and physiological roles of kainate receptors in the mammalian CNS
Calcium and neurotoxicity Localised increases in [Ca2+]trigger physiological events Excessive Ca2+loading activates processes that lead to cell death Neurotoxicity mediated by glutamate receptors is largely calcium dependent
Calcium and neurotoxicity Localised increases in [Ca2+]i trigger physiological events Excessive Ca2+ loading activates processes that lead to cell death Neurotoxicity mediated by glutamate receptors is largely calcium dependent