2020B10 Discuss the structure and function of the NMDA receptor and briefly describe the interaction of ketamine with this receptor

 

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

 

Effect of ketamine

Receptor

·  Non-competitive antagonist at PCP site

·  ↓Receptor activation

Cellular effect

·  ↓Ca2+-mediated cell activation

·  ↓2nd messenger signalling

·  ↓Gene transcription

Analgesic effect

·  ↓Receptor excitability = wind-up -> ↓hyperalgaesia, allodynia

·  ↓Synaptic reinforcement = long-term potentiation

·  ↓Acute somatic and neuropathic pain

·  ↓Opioid requirement

·  ↓Progression to chronic pain

·  Less utility once chronic pain established

Other use

·  Dissociative general anaesthesia, including single agent use

·  Poorly understood effect on cell toxicity

o   ↓Ca2+ mediated excitotoxicity

o   ↑Neuronal damage in young rodents

·  ? Beneficial effect in depression

 

 

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