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
(others: AMPA, kainate)

Location

·   Spinal cord: especially dorsal horn 2° nociceptive afferents

·   Brain: especially hippocampus

Structure

·   Transmembrane

·   2 x NR1 subunits (pore-forming)

·   1 x NR2A subunit (binds glutamate)

·   1 x NR2B (binds glycine)

Binding sites

·   Orthosteric: for glutamate

·   Coactivating: glycine

·   Phencyclidine: ketamine, PCP (antagonists)

·   Pore: blocked by Mg2+

·   N2O and Xe: site unknown (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 -> hyperalgaesia, allodynia

·   Long term -> synaptic reinforcement = LT potentiation

·   Mechanism: NMDA -> 2nd messenger and ↑gene transcription

·   ->hyperalgaesia, allodynia, chronic pain

Neuroplasticity

·   e.g. learning, memory

·   Repetition -> high frequency NMDA activation

·   Activity-dependent facilitation -> ↑excitability, synaptic reinforcement -> 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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