Lecture 3 - GABA Flashcards
How is GABA synthesised?
Synthesised from glutamate by the enzyme glutamate decarboxylase (throughout neuron by GAD67 and in nerve terminals by GAD65)
How is GABA transported into cells?
GAT1 and GAT3 transporters
How is GABA transported into vesicles?
VGAT transporters
What is the structure of the GABAa receptor?
Ionotropic Pentameric (5 subunits) 4 transmembrane domains, second one forms the ion channel N and C terminus both extracellular N terminus has cys-cys loop
What is the location and function of the GABAa receptor?
Postsynaptic only
Inhibitory as it allows chloride ion influx
What are the positive allosteric modulators of the GABAa receptor?
Benzodiazepines
Alcohol
Barbiturates
Neurosteroids
What is the subunit composition of the GABAa receptor?
Different compositions found in different parts of the brain
Most common is 2 alphas, 2 betas and a gamma or delta
Where does GABA bind to the GABAa receptor?
At the alpha/beta subunit interface
What is the structure of the GABAb receptor?
2 GPCRs (Obligate Dimer) 7 transmembrane domains Extracellular N terminus Intracellular C terminus GABAb-R1 and GABAb-R2
Where does GABA bind to the GABAb receptor?
Binds to the GABAb-R1 receptor
GABAb-R2 interacts with the intracellular G proteins
What is the location and function of the GABAb receptor?
Presynaptic and Postsynaptic
Inhibitory as coupled to Gi/o
Inhibits cAMP signalling
Inactivates presynaptic calcium channels, reducing neurotransmitter release
Activates postsynaptic GIRK channels, hyperpolarisation
Name an agonist of the GABAb receptor
GABA, Baclofen
Why don’t GABA receptors occur on dendritic spines?
Do not pass calcium therefore do not result in biochemical changes, only voltage changes
What is the shape of the IPSP caused by GABA and why is it like this?
Biphasic
Caused by ionotropic and metabotropic receptor types
Initial dip caused by GABAa
Later, prolonged dip caused by GABAb
What is the difference between wiring transmission and volume transmission?
Wiring transmission between compact, well-defined structures. Used by fast neurotransmitters. Localised responses
Volume transmission used by neuromodulators, diffuse to cover large areas
Name an agonist, competitive antagonist and non-competitve antagonist of the GABAa receptor
Agonists = GABA, Muscimol
Competitive antagonists = Bicuculline, GABAzine
Non competitive antagonists = Picrotoxin, U93631
Where do benzodiazepines bind to the GABAa receptor?
At the alpha-gamma subunit interface
What do benzodiazepines do to the GABAa receptor and what physical effects does this have?
Increases frequency of channel openings
Anticonvulsant
Anti anxiety
Promotes sleep
Name two BDZ-site inverse agonists and their uses
DMCM - Used to promote seizures
Flumazenil - used to treat BDZ overdoses
How do barbiturates and neurosteroids act differently to BDZs?
Different binding site
At low concs are positive allosteric modulators, at high concs directly activate receptor
Increases duration of channel openings
How do GABAb receptors modulate short term plasticity?
GABA released
Binds to presynaptic GABAb receptors (autoreceptors)
Inhibition of calcium channels
If a second action potential arrived in a short amount of time, less GABA is released
What are the possible subunits for the GABAa receptor?
Alpha Beta Gamma Delta Phi
