Ionotropic Glutamate Receptors 2024 PDF

Ligand-Gated Ion Channels- Ionotropic Glutamate receptors Dr Stephen Kelley Senior Lecturer in Pharmacology [email protected] 1  Learning outcomes Be able to discuss the structure and cellular and physiological fun...

Ligand-Gated Ion Channels- Ionotropic Glutamate receptors Dr Stephen Kelley Senior Lecturer in Pharmacology [email protected] 1  Learning outcomes Be able to discuss the structure and cellular and physiological function of ionotropic glutamate receptors. Be able to discuss drug action at ionotropic glutamate receptors. Recommended reading: See noted sections in the slides  The Ligand-Gated Ion Channel Receptors Cys-loop receptors- nicotinic acetylcholine receptors, 5- HT3 receptors, GABAA receptors, the strychnine sensitive glycine receptor and the zinc-activated channel (ZAC) o Ionotropic glutamate receptors- NMDA receptors, AMPA and kainate receptors P2X receptors Acid sensing ion channels 3 L-Glutamate (Glu) is the Principal Excitatory Neurotransmitter in the Central Nervous System O H N H H - O O O H 4  action potentials Glutamatergic The anaesthetic Ketamine acts as Neuro- Ca2+ Ca2+ an open channel Transmission blocker at NMDA receptors Glial GABA GAD Cell pre-synaptic Glu neuron Glutamate 5-HT Transporter Glutamate (Glu) Metabotropic Na+ Na+, Ca2+ Glu Receptor action (mGluR1) potentials PLC Gαq AMPA NMDA Receptor Excitation or Kainate Receptor DAG IP3 PIP2 + Ç[Na+] i Ç[Na+, Ca2+] i PKC Ç[Ca2+]i Dr Kelley 5 post-synaptic neuron  Sodium Valproate stimulates this enzyme O H CO2 N H H - O HO NH glutamate H O O O decarboxylase H GABA glutamate 6  Ionotropic Glutamate Receptors Glutamate Subunits Permeability Receptor NMDA GluN1, GluN2A, Na+, high Ca2+ Receptor GluN2B, GluN2C, GluN2D, GluN3A and GluN3B AMPA GluA1, GluA2, Na+, some Receptor GluA3 and GluA4 Ca2+ Kainate GluK1, GluK2 or Na+, some Receptor GluK3 Ca2+ 7  Ionotropic Glutamate Receptors: Basic Structure Tetramers- that means composed four protein subunits Like the cys-loop receptors, the ionotropic glutamate receptors can be either homo-oligomers (AMPA receptors) or hetero-oligomers (NMDA, kainate receptors ) All the receptors are gated by glutamate and mediate excitatory neurotransmission in the central nervous system 8 Ionotropic Glutamate Receptors: Basic Structure Adapted from Traynelis et al., 2010 and a more recent overview is in Hansen et al., 2021. Additional information in Medical Physiology (eBook), pp 468-472 and Rang and Dale’s Pharmacology, pp 510-517 9 Ionotropic Glutamate Receptors: Basic Structure 10 adapted from Traynelis et al., 2010 NMDA receptor – crystal structure 11 adapted from Karakas and Furukawa (2014) N-methyl-D-apartate (NMDA) receptors May be comprised of GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits Agonists include glutamate and NMDA Permeable to Na+, K+ and highly permeable to Ca2+ The NMDA receptor uniquely requires binding of both glutamate and the co-agonist glycine for activation The channel of the NMDA receptor is normally blocked by Mg2+. Following membrane depolarisation the Mg2+ ions are jettisoned and the channel then is able to conduct. 12 Ketamine Open channel blocker at the NMDA receptor Used in the induction and maintenance of anaesthesia Dissassociative anaesthesic 13 Amantidine Antiviral used to treat influenza, but it is also acts as a channel blocker at NMDA receptors Indicated for treatment of Parkinson’s disease 14 ion channels contributing to neuronal cell death during ischaemia 15 adapted from Weillinger et al., 2012 NMDA receptor subunit mutations GluN1 – Autosomal dominant non-syndromic intellectual disability GluN2A – Focal epilepsy, Landau-Kleffner syndrome, Rolandic epilepsy GluN2B – Mental retardation 16 www.guidetopharmacology.org α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid (AMPA)receptors and kainate receptors AMPA receptors are comprised of GluA1, GluA2, GluA3 and GluA4 subunits. Agonists for AMPA receptors include glutamate and AMPA. Kainate and domoic acid have low potency at AMPA receptors AMPA receptors are permeable to Na+ and K+ with little permeability to Ca2+ 17 Kainate receptors Kainate receptors can be expressed as homo- oligomers of GluK1, GluK2 or GluK3 subunits. GluK1-3 subunits can assemble into hetero- oligomers. Agonists for kainate receptors include glutamate, kainate and domoic acid Kainate receptors are permeable to Na+ and K+ with little permeability to Ca2+ 18 AMPA and Kainate receptor subunit mutations GluA3 – X-linked mental retardation, GluK2 – Mental retardation 19 www.guidetopharmacology.org GluD1 and GluD2 (glutamate receptor delta-1 and -2 subunits) ‘orphan’ receptor subunits –ligand not confirmed May be involved in synaptic plasticity 20 Drug Targets: AMPA, Kainate and NMDA receptors The big one- excitotoxcity from rise in intracellular Ca2+ from glutamate receptor activation. Neurotoxins- glutamate analogues domoic acid β-N- oxylaminoalanine (BOAA) and β-N-methylamino-L- alanine (BMAA). Ischaemic neuronal death- mediated by NMDA and AMPA receptors ‘PCP is a channel blocker for NMDA receptors- disassociative anaesthetic – ketamine also a channel blocker Mutations of glutamate receptors are associated with epilepsy Dr Kelley 21  Domoic Acid Poisoning Pseudo-nitzschia mussels domoic acid 22