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
(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 site: for glutamate

·   Coactivating site: glycine

·   Phencyclidine site: ketamine, PCP

·   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

 

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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