L12 - Glutamate

Question 1

Besides Glu, what other a.acid acts at Glu receptors

Answer 1

Aspartate

Question 2

How closely related to other NT are GluR?

Answer 2

Not very

Question 3

Is astrocyte more important for Glu or GABA?

Answer 3

Glu

Question 4

Co-agonist of NMDA receptor?

Answer 4

Glycine

Question 5

NMDA channel blockers - list 2

Answer 5

Phencyclidine (PCP) and ketamine

Question 6

Glycine site antagonist

Answer 6

Kynurenate

Question 7

Polyamine site antagonist

Answer 7

Ifenprodil

Question 8

iGluRs - subunits?

Answer 8

Pentameric structure but subunits don’t have 4 TM domains

Question 9

iGluRs are split into 2 major divisions

Answer 9

• NMDA R are voltage-dependent, mediate slower responses (synaptic plasticity), effects mediated by Ca2+ entry
• Non-NMDA (AMPA, kainite) mediate fast excitatory transmission

Question 10

Phencyclidine (PCP) effects

Answer 10

Disorientation, agitation, amnesia, euphoria, ataxia, delirium
*cross between psychedelics and tranquilisers

Question 11

PCP is a positive/negative allosteric modulator of NMDA receptors and works by?

Answer 11

Negative, blocks receptor to decrease Ca2+ influx

*A negative modulator (NAM) reduces the effects of the orthosteric ligand

Question 12

PCP is potentially neuroprotective but what’s the issue?

Answer 12

You might get anaesthesia and psychosis and may disrupt necessary excitatory transmission

Question 13

Ketamine is developed as an anaesthetic alternative to ?

Answer 13

PCP

Question 14

Why is ketamine a unique drug?

Answer 14

Combines hypnotic, analgesic, amnesic (no other drugs in clinical practice combines these three)

Question 15

Ketamine side effects?

Answer 15

Impairs all senses (dissociative anaesthesia), nausea, partial depressant of the respiratory system, elevates BP and HR, anaesthetic

Question 16

Ketamine is competitive/non-competitive NMDA receptor antagonist?

Answer 16

Non-competitive - channel blocker
*A competitive antagonist binds to the same site as the agonist but does not activate it, thus blocks the agonist’s action. A non-competitive antagonist binds to an allosteric (non-agonist) site on the receptor to prevent activation of the receptor.

Question 17

What types of opioid receptors does it bind to at high conc?

Answer 17

Mu and sigma

Question 18

mGluR _ groups _ subtypes

Answer 18

3 groups, 8 subtypes

Question 19

Conc of Glu in synapse is 1_M, in nerve is 10_M

Answer 19

Micro, milli

Question 20

Excitotoxicity involves excessive activation of?

Answer 20

iGluRs and ONLY group 1 mGluRs (Gq signalling where Ca2+ goes up, mGluR 2 and 3 are Gi)

Question 21

Riluzole

Answer 21

Anti-Glu used to treat ALS

* blocks TTX-sensitive sodium channels

Question 22

Memantine

Answer 22

Anti-parkinsonian, Inhibits NMDA receptor induced current

• Neuroprotection by low-affinity, uncompetitive, open-channel blockade of NMDA R
• Open channel blockade = spares normal neurotransmission
• Neuroprotective = decreases stroke damage
• Treats alzheimer’s disease, retinal degen/glaucoma, neuropathic pain, OCD

Question 23

Domoic acid poisoning

Answer 23

• Produced by planktonic algae eaten by shellfish and crabs
• Potent, selective kainate agonist in CNS and leads to sustained excitation and neurotoxicity
• Not destroyed by cooking or freezing
• Causes Amnesic Shellfish Poisoning in humans after ingestion

Question 24

Cycad toxicity - weak GluR agonist

Answer 24

• Bacteria in roots of cycad plants synthesize BMAA (beta methylamino L alanine) (weakly exototoxic)
• Implicated in “Guam dementia”: fatal, paralysing, neurodegenerative diseases like amyotropic lateral sclerosis (ALS) plus parkinsonism-dementia (PD)
• Conc in cycad seeds too low to be toxic but flying foxes eat the seeds - concentrating BMAA

Question 25

Problems with traditional blockade of NMDA R

Answer 25

• Normal excitatory function is vital
• Competitive antagonists block Glu signalling at all synapses
• Competitive antagonists most effective at low Glu conc
• High affinity = lasting effects = coma
• Moderate affinity = hallucination (PCP) or drowsiness (Ketamine)

Question 26

EAATs (Excitatory amino acid transporters)

Answer 26

5 subtypes 
1,2 - glial
3-5 - neuronal
*As there are no extracellular enzymes to metabolize Glu, it must be moved into cell to be metabolised
4 - Cerebellum
5 - retina only

Question 27

What is the problem with using competitive substrate at EAATs?

Answer 27

It heteroexchanges, forcing Glu out of the cell => excitotoxicity
Hence, use a non-transportable blocker so heteroexchange doesn’t occur

Question 28

Blockade of EAATs, antisense inhibition of EAATS or genetic KO of EAATS all lead to

Answer 28

Neuronal death