Glutamate

Question 1

what is NMDA composition

Answer 1

(1) 3TM subunits
(2) heterotetramers
(3) subunits: GluN1
GluN2A-D
GluN3A-B
(4) GluN1 and GluN2 or GluN3

Question 2

what does NMDA activated by

Answer 2

Activated by:
- glutamate
- glycine
- Vm above rest (Mg2+ block)

Question 3

how does NMDA receptor work

Answer 3

Normally activated in parallel with AMPA receptors
- Facilitates Ca2+-dependent excitatory signalling
- Mediates downstream Ca2+-dependent intracellular cascades
- e.g. Ca2+/calmodulin dependent kinase II (CaMKII) phosphorylation
of AMPA receptors, leading to LTP
- e.g. activation of BDNF leading to LTP

Question 4

How is the function of the NMDA receptor

Answer 4

• facilitates plasticity -> improves learning, memory, and cognition

Question 5

what does the over reaction of the NMDA receptor associated with

Answer 5

But overactivation is associated with:
- excitotoxicity -> neurodegeneration
- psychiatric / mood disorders

Question 6

give two products for the NMDA

Answer 6

Memantine – for Alzheimer’s disease
Ketamine – anaesthetic

Question 7

explain Mamantine

Answer 7

low affinity open channel blocker (non-competitive to agonist sites)
- blocks open channel in the presence of agonists (activated receptor)
- believed to selectively block pathological activation of NMDA receptors,
i.e., that mediated by elevated tonic levels of glutamate

Question 7

explain Katamine

Answer 7

potential for cardiac stimulation and respiratory depression
- potential for psychoactive effects (e.g. dissociation) -> “Special K”
- new indication for treatment-resistant depression
- S enantiomer formulated as esketamine nasal spray
- high affinity open channel blocker (non-competitive to agonist sites)
- blocks open channel in the presence of agonists (activated receptor)

Question 8

give an example for antagonists NMDA

Answer 8

Perampanel – for Epilepsy

Question 8

How does Perampanel work

Answer 8

indicated as adjunctive therapy for partial-onset and primary
generalized tonic-clonic seizures
- serious black-box warnings!
- Psychiatric and behavioural reactions
- Primarily aggression, hostility, irritability
- selective non-competitive antagonist to the AMPA receptor
(but precise mechanism “remains to be fully elucidated”)
- appears to act as a negative allosteric modulator (NAM)