Neurotransmitters Systems ll: GABA and Glycine (neuro) Flashcards
GABA intro
- gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS
- was first identified in mammalian nervous system in 1950
- in 1957, GABA was shown to inhibit action potential firing in crayfish neurons
- approx 1/3 of synapses utilise GABA as their neurotransmitter
- GABA most commonly found as an inhibitory neurotransmitter in local circuit interneurons
GABA synthesis and storage
- glutamate to GABA, using glutamate decarboxylase (GAD) and pyridoxal phosphate (derived from vitamin B6 co-factor)
- synthesised in nerve terminals
- transported into vesicles by vesicular inhibitory amino acid transporters (VIAAT)
- vesicles are round or oval
GABA re-uptake and degradation
reuptake:
- pre-synaptic terminal to post-synaptic neuron using GAT
- neurons and glial contain high-affinity Na+ dependant GABA re-uptake transporters (GATs):
- neurons = GAT-1
- glial cells = GAT-3
degradation:
- GABA to succinic semialdehyde using GABA transaminase (GABA-T)
- succinic semialdehyde to succinic acid, using succinic semialdehyde dehydrogenase (SSADH)
GABA receptors
- GABA binds at both ionotropic and metabotropic GABA receptors
- ionotropic = GABAa receptor
- metabotropic = GABAb receptor
GABAa receptor
ligand-gated Cl- channel: - extracellular: ligand binding between closed and open - intracellular: release of Cl- ions between closed and open pentameric structure: - six alpha subtypes (a1-6) - three beta subtypes (b1-3) - three gamma subtypes (g1-3) - also delta, epsilon, pi, omega subunits - 2a2bg most common configuration multiple binding sites: - agonists/antagonists eg GABA - benzodiazepine binding site - channel blockers eg picrotoxin - channel modulations eg GA - allosteric modulators eg barbiturates
GABAb receptor
- G-protein coupled receptor (GPCR)
- dimers: heteromers GABAb1 and GABAb2
Inhibitory neurotransmitters and hyperpolarisation
- inhibitory neurotransmitters (eg GABA) can cause neuronal membrane hyperpolarisation - displacement of a membrane potential towards a more negative value
Cerebellum
- the cerebellum (‘little brain’) is a prominent hindbrain structure
- accounts for approx 10% of the human brains volume
function: - does not initiate movement but detects differences in ‘motor error’ between an intended movement and actual movement
- important in synchronisation of movement with musical rhythm
- may be widespread across the animal kingdom
GABA projections in cerebellum
- Purkinje cells are a class of GABAergic neurons that comprise the principle projection neurons of the cerebellar cortex
- they have elaborate dendritic trees that receive convergent input from cells in the molecular layer
- they send GABAergic projections to deep cerebellar neurons
- their output to the deep cerebellar neurons generates an error connection signal that can modify movements
- provides the basis for real time control of precise and synchronous movement
Balance of GABA and glutamate
- GABA and glutamate are the major neurotransmitters in the brain
- both work together to control the brain’s overall level of excitation
- in one step, the major excitatory neurotransmitter in the brain (glutamate) is converted into the major inhibitory neurotransmitter in the brain (GABA)
- this is done using glutamate decarboxylase (GAD) and pyridoxal phosphate (derived from vitB, cofactor)
Epilepsy (GABA)
- a brain disorder characterised by periodic and unpredictable seizures mediated by the rhythmic firing of large groups of neurons
- too much excitation means that there needs to be an increase in inhibition to combat this
- drugs which do this are:
- GABAA receptor enhancers - barbiturates and benzodiazepines
- GAT blockers - Tiagabine
- GABA-transaminase inhibitor - Vigabatrine
- GAD modulators - Gabapentin and Valproate
- Prodrug - Progabide
- other anti-epileptics directly decrease excitation instead
Anxiety (GABA)
- can be defined as a feeling of unease (eg worry or fear), which can range from mild to severe
- anxiety disorders (eg generalised anxiety disorder, panic disorder)
- anxiolytics (eg benzodiazepines - GABAA receptor)
Glycine
- is the second major inhibitory neurotransmitter in the CNS
- first identified in spinal cord and brainstem in 1965
- in 1967, glycine was shown to inhibit action potential firing in spinal neurons
- most commonly found as an inhibitory neurotransmitter in the ventral horn (location for spinal interneuron terminals)
- our understanding of glycine receptor is lagging behind the GABA receptors - in part due to limited allosteric modulators of the receptor
Glycine synthesis
- 3-phosphoglycerate (glycolysis) -> serine
- serine -> glycine, using serine hydroxymethyl-transferase
- synthesised in nerve terminals
- transported into vesicles by vesicular inhibitory amino acid transporters (VIAAT)
- round vesicles = glutamate
- oval vesicles = GABA, glycine
Glycine re-uptake and degradation
reuptake:
- neurons and glial contain high-affinity Na+ dependant glycine re-uptake transporters (GlyTs) that transport glycine from presynaptic terminal to postsynaptic neuron
- glial cells contain GlyT-1
- neurons contain GlyT-2
degradation:
- various enzymes responsible for breakdown of glycine - including reversal of glycine biosynthesis
- glycine -> serine using serine hydroxymethyl-transferase
