GABA and Glutamate 1 Flashcards
GABA (g-aminobutyric acid)
is the main inhibitory neurotransmitter in the brain
(glycine in the spinal cord)
Unique role as neurotransmitter
Controls GABAergic neurones
Glutamate (glutamic acid)
is the main excitatory neurotransmitter in the brain
CNS transmitter
Controls Glutamatergic neurones
Synaptic plasticity
Has a role in stroke, epilepsy, neurodegeneration
Glutamate is synthesised by amination of a-ketoglutaric acid (from TCA cycle) or from glutamine
Most body cells receive Glu and GABA
at corresponding receptors and the proportions control activity
Glutamate receptors
Open: ions flow in – pos ions excitatory from glutamate
- neg ions inhibitory from GABA
EPSP – excitatory post synaptic potential
IPSP - inhibitory post synaptic potential
NMDA receptors
The receptor consists of s Calcium channel controlled by a Mg ion blocking it
Glutamate binding site with a glycine coagonist
PSP – opens the channel releasing the Mg ion, depolarisation occurs
N methyl D aspartate (NMDA) is a synthetic drug that activates channel
NMDA Possesses many surface binding sites for regulation
Antibody subunits were developed synthetically by Chazot (shown as R2 chemicals on diagram in notes)
Glutamate and excitotoxicity
Linked to stroke, trauma, epilepsy, neurodegenerative conditions
Share a final common destructive metabolic pathway called ‘excitotoxicity’
150,000 stroke cases per year in the UK
Emergency stroke care aims to save the ‘penumbra’ a zone of reversible ischemia around the core of irreversible infarction salvagable in the first few hours of ischemic stroke onset
A stroke involves:
Interruption of blood supply to the brain
Cell death (necrosis) in the core
Excessive glutamate release in penumbra
Sustained activation of glutamate receptors
Excitotoxicity – uncontrolled entry of Ca2+ and Na+
Cascade of toxic metabolic events triggered by high [Ca2+]
Synaptic plasticity
Long term changes in synaptic function
The basis of learning and memory?
Enhanced transmitter release
Increased sensitivity and numbers of receptors
Increased protein synthesis
Structural changes
Synaptic plasticity reduces with old age
This occurs due to a reduction in spines and hence reduction in synapses and processing power
This can also occur in younger individuals if the brain is not used enough
Mechanism of long-term potential (LTP)
Synaptic plasticity was discovered in glutamatergenic pathways in the 1960’s
Kinase enzymes phosphorylate proteins – this is a regulatory mechanism
More receptors = more healthy = more reactive
Drugs acting on Glu response are NMDA receptor antagonists
They block excitotoxicity
Were thought to have potential to treat strokes from lab animal observations
However in human trials were found to cause psychotic effects similar to excessive ketamine use
Memantine has been found to be a more subtle blocker and may have applications in Alzheimers
(see 8 step LTP process diagram in notes)
Drugs acting on Glu receptors
NMDA receptor antagonists (block excitotoxicity)
Dizocilpine (MK-801); ketamine; memantine;
Phencyclidine
Glycine site antagonists
Antagonists of metabotropic receptors
GABAergic neurotransmission
~20% neurons in the brain are GABAergic
GABA is involved in anxiety and epilepsy
It has an amnaesiac effect
Resulting in memory or action inhibition
GABA metabolism
Glutamate -> GABA -> Succinic semialdehyde -> Succinate
GABA receptors
GABA A – ionotropic; pentameric; 16 different subunits
GABA C – ionotropic; primarily retinal; r-subunits
GABA B – metabotropic effects; presynaptic and postsynaptic; ↓Ca2+ entry; ↑K+ entry
interneurons
make up more than 99% of the neurons in the human body
They act to relay sensory information and regulate motor function, tend to have an inhibitory effect and are usually short
G-protein coupled receptors
e.g dopamine and adrenaline receptors
Beta-blockers are an example of g protein receptor blockers
