Neurosurgery notes/Anatomy/Peripheral nerves anatomy/Channels/Glutamate

Glutamate

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Channels

Glutamate

  • The primary excitatory neurotransmitter in the human brain

Receptors

Receptor Type
Typical Agonists
Channel Permeant Ions
Clinical Role / Relevance
AMPA
Glutamate, AMPA
Na+^++, K+^++, Ca2+^2+2+*
Epilepsy, learning & memory; antagonists for seizures
NMDA
Glutamate, NMDA, Glycine
Na+^++, K+^++, Ca2+^2+2+
LTP, excitotoxicity; memantine & ketamine for CNS diseases
Kainate
Glutamate, Kainic acid
Na+^++, K+^++, (Ca2+^2+2+)
Synaptic modulation, epilepsy models
Metabotropic
Glutamate, DHPG, LY354740
Indirectly modulates various ions
Psychiatric/neuro diseases; research for targeted modulation

Ionotropic Glutamate Receptors (iGluRs)

  • General
    • All are non selective cation channels
    • Na+ and K+, and in some cases small amounts of Ca2+

NMDA receptors (activated by NMDA)

  • The NMDA receptor is ionotropic and controls a ligand-gated ion channel.
  • NMDA receptors contain binding sites for glutamate and the co-activator glycine, as well as an Mg2+-binding site in the pore of the channel.
    • Glycine itself is an inhibitory neurotransmitter via Cl− channels
  • Activated by:
    • Glutamate (endogenous, required)
    • Requires glycine or D-serine as co-agonist
    • Synthetic
      • NMDA
      • Ketamine
        • An NMDA antagonist, it is used as a sedative, anesthetic, off-label as an antidepressant, or recreationally as a hallucinogenic drug of abuse.
      • Phencyclidine (PCP)
        • An NMDA antagonist. It is used recreationally as a hallucinogenic, depersonalizing, euphoric drug of abuse. It reportedly causes homicidal and suicidal impulses in users. Users will characteristically experience nystagmus on physical exam.
      • Ethanol
        • A common recreational drug, it modulates NMDA receptors through complex mechanisms.
      • Memantine
        • An uncompetitive NMDA antagonist, this drug is used in the treatment of Alzheimer disease and off-label for Huntington disease.
      • Amantadine
        • An NMDA antagonist used in the treatment of Parkinson disease and off-label for Huntington disease.
      • Magnesium
        • This naturally occurs in the transmembrane ion channel of the NMDA receptor. It is used to prevent migraines and abort migraine aura, prevent seizures in preeclampsia, and as a neuroprotective agent administered to mothers of premature infants to prevent neonatal brain damage.
      • Methadone:
        • A mu-opioid agonist and NMDA antagonist used in the treatment of opioid addiction.
  • Channel permeant ions:
    • Na++, K++, and notably Ca2+
      • Ca2+ can act as a second messenger to activate intracellular signalling cascades → allows processes of long-term potentiation, synaptic plasticity, and memory formation
    • At hyperpolarized potentials, the electrical driving force on Mg2+ drives this ion into the pore of the receptor and blocks it.
  • Clinical relevance:
    • Key in long-term potentiation (LTP), synaptic plasticity, development
    • Excessive activity: Excitotoxicity, involved in stroke, neurodegeneration (Alzheimer's, Huntington’s)
    • Drugs (antagonists): Ketamine (anesthesia, depression), Memantine (Alzheimer’s disease)
notion image

AMPA receptors (activated by AMPA)

  • Activated by:
    • Glutamate (endogenous)
    • AMPA (specific agonist)
    • Synthetic agonists: Quisqualate, willardiine derivatives
  • Channel permeant ions:
    • Mainly Na++ and K++; some subtypes allow Ca2+2+ if they lack GluA2
  • Clinical relevance:
    • Crucial for fast excitatory neurotransmission and synaptic plasticity (learning, memory)
    • Overactivation: Implicated in epilepsy, ischemia (brain injury)
    • Drugs: Perampanel (antagonist) treats epilepsy

Kainate receptors (activated by kainic acid)

  • Activated by:
    • Glutamate
    • Kainic acid (potent agonist)
    • ATPA and willardiine derivatives
  • Channel permeant ions:
    • Na++ and K++; some allow limited Ca2+2+
  • Clinical relevance:
    • Modulate synaptic transmission, can be involved in epilepsy (kainic acid induces seizures in models)
    • Less targeted clinically; research ongoing for epilepsy and pain modulation

Metabotropic glutamate receptor (mGluRs)

  • Groups & Agonists:
    • Group I (mGluR1, mGluR5): Activated by glutamate, DHPG (agonist)
    • Group II (mGluR2, mGluR3): Activated by glutamate, LY354740 (agonist)
    • Group III (mGluR4, mGluR6, mGluR7, mGluR8): Activated by glutamate, L-AP4 (agonist)
  • Indirectly modulate:
    • K++, Ca2+2+ channels, and synaptic release
  • Clinical relevance:
    • Targets for anxiety, depression, schizophrenia, Parkinson’s, and pain
    • Novel drugs (orthosteric/allosteric modulators) under investigation for neuropsychiatric and neurodegenerative disorders