Inhibitory Amino Acid Neurotransmitters Flashcards
How is GABA synthesised ?
Made from glutamate
Glutamate is converted to GABA by glutamate decarboxylase (GAD) - gad is inhibited by allylglycine
What are examples of inhibitory amino acid neurotransmitters ?
GABA - main inhibitory one in the brain
Glycine - main inhibitory one in the spinal cord
Non-essential amino acids
How is GABA broken down ?
GABA is broken down to succinic semialdehyde by GABA aminotransferase (GABA-T) - this process requires the conversion of alpha-ketoglutarate to glutamate
GABA-T is mainly in mitochondria
What inhibits GABA-T ?
Aminooxyacetic acid and vigabatrin
- these inhibit the breakdown of GABA
What happens to the succinic semialdehyde ?
It’s broken down to succinate by succinic semialdehyde dehydrogenase
Succinate can be used as an intermediate in the Krebs cycle to produce GABA or glutamate
What is vigabatrin used to treat ?
Used to treat epilepsy because it reduces the breakdown of GABA so increases the amount of GABA
What 2 substances can make GABA ?
Glutamate or succinate
What are the GABA receptors ?
GABAa - ionotropic - Cl-
GABAb - GPCR - 7 transmembrane domain
GABAc - ionotropic - Cl- - mainly in retinas
What effect does GABA binding to GABAa receptors in adult cells ?
Hyperpolarisation because it causes an influx of Cl-
What are the subunits of a GABA receptor like ?
Each subunit is 50-60kDa and there overall molecular weight of the receptor is 275kDa so it has 5 subunits
6 classes of subunits: alpha, beta, gamma, epsilon, delta and roe
At least 19 different polypeptide subunits so there is a lot of diversity of GABA receptors
What is the subunit diversity like in GABAa receptors ?
Subunits within each group have 70% similarity and the subunits between different groups have 30% similarity
What loop binds GABA and what domain makes the pore ?
Cys loop and domain 2 is thought to make the pore lining
What are the 5 distinct binding sites on a GABAa receptor ?
GABA site Benzodiazepine site Steroid site - anaesthetics Barbiturate site - depressants Picrotoxin site -convulsants
What happens when benzodiazepines bind to GABAa receptors ?
It enhances the effects of GABA binding
What happens when picrotoxin binds to GABAa receptors ?
The binding site is within the pore of the channel and it blocks the receptor preventing its inhibitory activity
What effects occur when GABAb is stimulated ?
Inhibits adenyl Cyclase
Stimulates phospholipase a2
Activates some potassium channels - voltage gated ones
Inhibits calcium channels on presynaptic nerve terminal preventing further neurotransmitter release
Causes long slow inhibition
What are agonists at GABAb receptors ?
Baclofen and saclofen
- muscle relaxant and antispastic agent
What are antagonists for GABAb receptors ?
Phacolfen and 2-hydroxysaclofen
Where are glycine receptors located ?
Grey matter of spinal cord Medulla Midbrain Hypothalamus Thalamus
How is glycine synthesised ?
Serine converted to glycine by serine hydroxymethyltransferase
How is glycine taken up from the synaptic cleft ?
By sodium dependent transporters - GLYT 1 and GLYT 2
How is glycine packaged into vesicles ?
Can’t find a specific tranpsorter for glycine so it is though that it uses GABA transporter
From rat spinal cord what is the structure of glycine receptors like ?
Strychnine binding site inhibits the glycine receptor
3 proteins- alpha subunit - 48kDa, beta subunit- 58kDa and gephyrin- 93kDa
There are 3 isoforms of alpha subunit - 1, 2, and 3
What is the structure of the glycine receptor like ?
4 transmembrane domains Part of ligand gated superfamily Large n terminal extracellular loop Larger intracellular loop m3-m4 Pentamer - adult = 3 alpha and 2 beta while fetal are alpha-2 homomers
What is the purpose of gephyrin in the glycine receptor ?
Involved in anchoring the receptor to a specific place in the cell
What is the glycine receptor involved in ?
Reflex response
Causes reciprocal inhibition - voluntary muscle control and sensory processing
What happens in hyperperplexia ?
It’s an exaggerated reflex
Often caused by a mutation in the glycine receptor
Patients suffering from this will go into a complete state of shock for several minutes upon a shocking stimuli occurring
What is hyperperplexia treated with ?
Benzodiazepine
What increases glycine release ?
Tetanus toxin
