2020B Question 10
Discuss the structure and function of the NMDA receptor and briefly describe the interaction of ketamine with this receptor
Examiner Report
This question was simple in scope, in that it asked about a common and important CNS receptor, and the way in which ketamine interacts with that receptor.
The NMDA receptor is a voltage-sensitive ligand-gated receptor. There is some difference in detail between the recommended textbooks regarding sub-unit structure, so variations were accepted. Detail regarding the AMPA receptor in providing initial depolarization, the Mg2+ plug, glutamate and glycine binding, and ionic currents were necessary.
Many candidates offered that the NMDA receptor caused long-term potentiation and various chronic pain phenomena, but very few attempted to describe a mechanism that related to NMDA activation and intracellular events.
There were some good descriptions of where ketamine bound to NMDA, and the effect it had.
A number of candidates did not offer that one of the effects of ketamine was general anaesthesia.
There were a number of repeated errors that showed lack of general understanding. The NMDA is not a metabotropic (G-protein linked) receptor. Substance P and the NK-1 receptor are not involved in NMDA activation. The influx of Cl- ions is not excitatory.
Pharmacokinetic data for ketamine was neither asked for nor rewarded. Organ-based pharmacodynamic information for ketamine did not receive marks..
Model Answer
Structure:
- General description
- Activation process
- Physiological role
General Description
| Factor | Detail |
|---|---|
| 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
| Stage | Detail |
|---|---|
| 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
| Stage | Detail |
|---|---|
| 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 - ↓ Ca2+ mediated excitotoxicity - ↑ Neuronal damage in young rodents - ?Beneficial effect in depression |