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GABA, glutamate receptors and their modulation
This document provides an overview of glutamate and GABA, their receptors and therapeutic applications. It discusses the synthesis, storage, release and termination of glutamate and GABA in the central nervous system. It describes the ionotropic and metabotropic glutamate receptors and GABAA and GABAB receptors. It also discusses conditions associated with glutamate like seizures, neurodegenerative diseases and stroke. Finally, it outlines current and upcoming therapeutic agents that target glutamate and GABA receptors and their uses, mechanisms and adverse effects.
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GABA, glutamate receptors and their modulation
- 1. GLUTAMATE & GABA RECEPTORSAND THERAPEUTIC APPLICATIONS
- 2. OUTLINE • INTRODUCTION • HISTORY •GLUTAMATE : Synthesis, storage, release, termination Glutamate receptors Synaptic plasticity, ltp/ltd, excitotoxicity Therapeutic applications & upcoming agents • γ-AMINO BUTYRIC ACID: Synthesis, storage, release, termination Gaba receptors Therapeutic applications • CONCLUSION
- 3. INTRODUCTION: AMINO ACIDTRANSMITTERS •CNS- high concentrations of certain amino acids. •Dicarboxylic vs Monocarboxylic amino acids. •Terms : Neurotransmitters vs Neuromodulators.
- 4. HISTORY •1950s - littlereason to look further. •γ-aminobutyric acid (GABA) - (1950s) transmitter role postulated. •Curtis’s group - glutamate produced a strong excitatory effect. •1960s - GABA and excitatory amino acids (EAAs) ? Mere pharmacological curiosities. •1970s – Glycine. •Discovery of EAA antagonists.
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- 8. GLUTAMATE RECEPTORS • IONOTROPICGLUTAMATE RECEPTORS • 4 subunits assembly, each with ‘pore loop’. • 16 different receptor subunits – IUPHAR recommended terminology. • NMDA receptors - 7 types of subunits (GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, GluN3B). •AMPA receptors – 4 types of subunits (GluA1–4). • Kainate receptors – 5 types of subunits (GluK1–5).
- 9. •Receptors comprising differentsubunits; differ in characteristics, e.g. AMPA receptors lacking GluA2. •NMDA – slow excitatory. AMPA, kainate receptors - fast excitatory. •NMDA and Kainate receptors – also pre-synaptic. •Cortex, basal ganglia and sensory pathways. •NMDA, AMPA – generally co-localised.
- 10. NMDA receptors: Special features •Highlypermeable to Ca2+. •Mg2+. •Glutamate + simultaneous depolarization (AMPA/kainate). •Role of glycine.
- 13. •METABOTROPIC GLUTAMATE RECEPTORS •8different metabotropic glutamate receptors (mGlu1–8). •Divided into three groups. •Group 1 mGlu receptors located post-synaptically and are largely excitatory. •Group 2 and 3 mGlu receptors presynaptic receptors ↓ synaptic transmission and neuronal excitability.
- 15. SYNAPTIC PLASTICITY &LONG-TERM POTENTIATION (LTP) •NMDA, mGlu receptors – Long term adaptive changes. •Long-term potentiation : prolonged enhancement of synaptic transmission following presynaptic stimulation. •Counterpart - long-term depression (LTD).
- 18. EXCITOTOXICITY •High concentrations ofglutamate → neuronal cell death. •Glutamate-mediated excitotoxicity may underlie the damage occurring after ischemia or hypoglycemia in the brain. •NMDA receptor antagonists. •? Etiology of chronic neurodegenerative diseases.
- 20. DISEASE ASSOCIATIONS WITHGLUTAMATE Seizures ADHD Autism Neurodegenerative diseases Multiple Sclerosis Rasmussen’s Encephalitis Stroke
- 21. THERAPEUTIC APPLICATIONS KETAMINE •Congener ofPhencyclidine. •MOA : NMDA channel blocker and … •Uses : “Dissociative Anesthesia” (hypotensive. Asthmatic. Pediatric procedures) •A/E : Hallucinations, Emergence Delirium, Amnesia, ↑ ICT, ↑ HR, Nausea, Vomiting, ↑IOP, Erythema, Rash.
- 22. MEMANTINE •NMDA Channel blocker,↓ excitotoxicity. •Uses : Moderate to Severe Alzheimer’s Disease. •A/E : Confusion, Dizziness, Drowsiness, Headache, insomnia, agitation. FELBAMATE •NMDA Blocker, +ve modulation of GABA-R. •Uses : Severe Refr. Partial Seizures, Lennox-Gastaut Syn. •A/E : ↓ appetite, vomiting, headache, aplastic anemia, liver failure.
- 23. TOPIRAMATE •AMPA-kainate antag. •Uses :Initial monotherapy & adj. therapy for partial onset/ primary GTCS, L-G Syndr, Migraine. •A/E : Fatigue, Weight loss, nervousness, renal calculi. ACAMPROSATE •Alcoholism. A/E – Diarrhea, allergy, headache, insomnia. RILUZOLE •Amyotrophic Lateral Sclerosis. •Modest ↑ in survival.
- 24. UPCOMING AGENTS •Analgesic :TEZAMPANEL : AMPA-Kainate Antagonist ; Phase III (Ac. Migraine) •ALS : TALAMPANEL : AMPA Antag. ; ALS negative results. •Seizure Disorder: PERAMPANEL : AMPA Antag. ; FDA – 2012 but role unclear. A/E – Suicidal thoughts, dizziness, vertigo, aggression, slurred speech, abuse liability.
- 25. • Stroke: NBQX: AMPA-Kainate Antag ; Pre Clinical TRAXOPRODIL : NMDA Antag. ; QT prolongation. • Neurodegen. RADIPRODIL :NMDA Antag.; Pre-Clin (Parkinson’s) REMACEMIDE:NMDA Antag.;Huntington(III),Park(II) FARAMPATOR : AMPA + modulator ; Alzheimer’s (I) PIRACETAM : Ampakine ; Dementia, not approved.
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- 29. GABA RECEPTORS GABAA (IONOTROPIC)RECEPTORS • IUPHAR Recommendation for GABAC. • Pentamers; 19 different subunits : (α1–6, β1–3, γ1–3, δ, ε, θ, π and ρ1–3). • α1β2γ2 - the most abundant. • α-β-α-β-γ
- 32. GABAB (METABOTROPIC) RECEPTORS •Gi- inhibit adenylyl cyclase, activate K+ channels, and reduce Ca2+ conductance.
- 34. THERAPEUTIC APPLICATIONS Drug/ ClassMechanism Use Adverse Effects BARBITURATES ↑ Duration GABAA gated Chloride Channel Anesthesia, Anticonvulsant, hyperbilirubinemia, Sedative-Hypnotics Distortion of Sleep Architecture, Learning and Memory impairment, respiratory depression, abuse, laryngeal edema, hypersensitivity. BENZODIAZEPINES ↑ Frequency GABAA gated Chloride Channel Anxiety, Insomnia, Induction, Sk muscle relaxation, Anticonvulsant, Alc Withdrawal Drowsiness, fatigue, disorientation, lethargy, respiratory depression, abuse, impaired memory and learning, date rape Z-DRUGS Agonist at modulatory site at GABAA R to which BZD bind Insomnia Rebound insomnia, hangover are less. Headache, daytime drowsiness, nightmares at high doses.
- 35. Drug/ Class MechanismUse Adverse Effects ETOMIDATE GABAA Agonist Induction of Anesthesia Nausea, Vomiting, Suppression of corticosteroid synthesis, Pain on injection, seizures. PROPOFOL GABAA Agonist Induction and maintenance, status epi Irregular heart rate, Hypotension, Burning sensation at site of injection, Apnea, seizures, addiction, Propofol Infusion Syndrome (PRIS). FLUMAZENIL Selective BZD Receptor Antagonist Suspected BZD overdose, reversal of sedative effects Convulsions , dizziness, injection site pain, increased sweating, headache, visual disturbances.
- 36. Drug/ Class MechanismUse Adverse Effects BACLOFEN GABAB Agonist Spastic movement disorders Vomiting, sedation, respiratory depression, seizures, Withdrawal syndrome, abuse potential. TIAGABINE GABA Reuptake Inhibitor Adj. t/t of partial seizures Dizziness, memory imp., tremor, headache, diarrhea, depression VALPROATE GABA Transaminase Inhibitor Epilepsy, Psy. Disorders, Migraine Wt gain, alopecia, tremors, hepatic necrosis, pancreatitis, NTD. VIGABATRIN GABA Transaminase Inhibitor Infantile Spasm Retinal atrophy, confusion, fatigue, wt gain, diarrhea, irritability.
- 37. PREGABALIN & GABAPENTIN GABA analogues Partial seizures (inaddn. to other drugs), Neuropathic pain Drowsiness, dizziness, ataxia, fatigue.
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Editor's Notes
- #4 Neurohormones Neuropeptides Neurotrophic Factors
- #7 Transmitter substances are marked with green boxes. GABA-T, GABA transaminase; GAD, glutamic acid decarboxylase
- #9 Red rectangles represent α-helices. Blue hairpins are pore loop (P) domains (through which ions pass)
- #11 Nmda antagonists – AP 5 (2-amino-5-phosphonopentanoic acid); CPP, 3-(2-carboxypirazin-4-yl)-propyl-1-phosphonic acid;
- #17 Memory strengthening occurs due to strengthening of existing synapses.
- #19 The frequency and pattern of synaptic stimulation may dictate whether a synapse undergoes LTP or LTD Brief activation of an excitatory pathway can produce what is known as long-term depression (LTD) of synaptic transmission in many areas of the brain. LTD is induced by a minimum level of postsynaptic depolarization and simultaneous increase in the intracellular calcium concentration at the postsynaptic neuron. D-serine release by astrocytes has been found to lead to a significant reduction of LTD in the hippocampus
- #21 Mechanisms contributing to neuronal injury during ischemia-reperfusion. Several pathways contribute to excitotoxic neuronal injury in ischemia, with excess cytosolic Ca2+ playing a precipitating role. DAG, diacylglycerol; GluR, AMPA/kainate type of glutamate receptors; IP3, inositol trisphosphate; mGluR, metabotropic glutamate receptor; NMDA-R, N—methyl- D- aspartate receptor; O2-, superoxide radical; PIP2, phophatidyinositol 4,5-bisphosphate; PKC, protein kinase C; PL, phospholipids, PL phospholipase, VSCC, voltage- sensitive Ca2+ channel. COX, cyclooxygenase; LOX, lipoxygenase; NCX, NA+/Ca2+ exchanger; mtPTP, mitochondrial permeability transition pore
- #27 NMDA receptors require glycine as well as NMDA to activate them, so blocking of the glycine site is an alternative way to produce antagonism. Kynurenic acid and the more potent analogue 7-chloro-kynurenic acid act in this way, as do various compounds currently in development. Overall, the promise foreseen for ionotropic glutamate receptor antagonists in the clinic has simply not, so far, been fulflled. The problem may be that glutamate is such a ubiquitous and multifunctional mediator—involved, it seems, in almost every aspect of brain function—that attempting to improve a specifc malfunction by flooding the brain with a compound that affects the glutamate system in some way is just too crude a strategy.
- #29 Transmitter substances are marked with green boxes. GABA-T, GABA transaminase; GAD, glutamic acid decarboxylase
- #36 Uses, a/e .Agonists/: ethanol (positive allo. modulator), barbiturates, benzodiazepines, carisoprodol, chloral hydrate, etaqualone, etomidate, glutethimide, kava, methaqualone, muscimol, neuroactive steroids, z-drugs, propofol, skullcap, valerian, theanine, volatile/inhaled anaesthetics. Antagonists/negative allosteric modulators: bicuculline, cicutoxin, flumazenil, furosemide, gabazine, oenanthotoxin, picrotoxin, ?PTZ, Ro15-4513, thujone, amentoflavone.
- #37 INHALED ANESTHETICS
- #38 GABAB receptor ligands. Agonists: baclofen, GBL (lactone), GHB, phenibut (dietary supplement). Antagonists: phaclofen, saclofen. (experimental) GABA reuptake inhibitors: deramciclane, hyperforin, tiagabine. GABA-transaminase inhibitors: gabaculine, phenelzine, valproate, vigabatrin, lemon balm (Melissa officinalis). GABA analogues: pregabalin , gabapentin. Neurosteroids?