2003B15 Briefly describe the N-methyl d-aspartate (NMDA) receptor
and its physiological role in the central nervous system.

 

List:

·        General description

·        Activation process

·        Physiological role

 

General description:

Type

·   Ligand-gated voltage-dependent glutamate receptor
(i.e. both are required for its activation)

·   Others: AMPA, kainate)

Location

·   Spinal cord: especially dorsal horn 2° nociceptive afferents

·   Brain: especially hippocampus

Structure

·   Transmembrane, tetrameric (in vivo)

·   2 x NR1 subunits (obligatory) – binds glycine

·   2 x NR2 subunits (modulatory) – binds glutamate

·   Central ion channel pore with Mg2+ plug

Binding sites

·   Glutamate site (agonist)

·   Glycine site (coagonist)

·   Phencyclidine site (within the pore): ketamine, PCP (non-competitive antagonists)

·   N2O and Xe: site unknown (non-competitive antagonists)

 

Activation process:

1.Priming

·   Activation of adjacent AMPA or NK-1 receptors

·   Partial depolarisation -> removal of Mg2+ plug

2.Coactivation

·   Binding of glycine

3.Activation

·   Binding of glutamate

·   Ion flux (Ca2+ influx > Na+ influx = K+ efflux)

·   Cell-dependent downstream effects

 

Physiological role:

Central sensitisation

·   Gain of function of wide dynamic range 2° afferents at the dorsal horn

·   Inflamed tissue, damaged nerve -> NMDA activation +++

·   Short term: ↑receptor excitability = wind up

·   Long term: ↑↓gene transcription -> synaptic reinforcement = potentiation

·   Hence hyperalgaesia, allodynia, chronic pain

Neuroplasticity

·   e.g. learning, memory

·   Repetition -> high frequency NMDA activation

·   Activity-dependent facilitation -> long-term potentiation

·   Activity-dependent inhibition -> long-term depression

Excitotoxicity

·   Ischaemia -> failure of ion homeostasis -> depolarisation -> release of glutamate

·   NMDA activation+++ -> ↑ICF [Ca2+]

·   ↑Activity of lytic enzymes, apoptosis

·   Mitochondrial dysfunction, further ↓[ATP]

 

 

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