Topic 12: GABA and Glycine Flashcards
What is gamma-amino butyric acid (GABA)?
GABA is the main inhibitory neurotransmitter in the CNS (10-40% of neurons in cortex, hippocampus, and substantia nigra)
GABA increases the conductance of chloride ions across cell membranes
Glycine has comparable but limited function as an inhibitory neurotransmitter
How is GABA synthesized?
glutamate is synthesized into GABA by glutamic acid decarboxylase (GAD)
What is the vesicular transport of GABA?
GABA and glycine share a vesicular transporter
vesicular GABA transporter (VGAT) or vesicular inhibitory amino acid transporter (IAAT)
VGAT identifies both GABAergic and glycinergic neurons in the CNS
In what way are inhibitors of GABA convulsants?
GAD has several antagonists used experimentally: allylglycine, thiosemicarbazone, and 3-mercaptopropionic acid
inhibition of GAD decreases GABA levels and leads to convulsive activity
many drugs that decrease GABAergic activity are limited in use to in vitro studies
What are GABA transporters?
GABA transporters (GAT) are found on astrocyte and neuronal membranes at the synapse
GAT-1 is located on neurons and astrocytes
Gat-2 and -3 are principally astrocytic
What are GABAergic AEDs?
drugs that increase GABA activity are anticonvulsant
tiagabine is a selective antagonist of GAT-1 and elevates GABA levels in the synapse
Tiagabine (Gabitril) is approved as a adjunctive AED for epilepsy
vigabatrin is a irreversible inhibitor of GABA-T and elevates GABA levels in the brain by blocking breakdown
Vigabratrin (Sabril) is approved as an adjunctive or primary AED for epilepsy
In what way is GABA widespread through the brain?
GABA is widely used in inhibitory interneurons throughout the brain
chandelier cells of the cortex synapse onto the axonal initial segment of pyramidal cells
basket cells of the cerebellum, hippocampus, and cortex form axo-somatic synapses onto target cells
What are the types of synapses formed at GABAergic neurons?
in addition to axo-dendritic synapses GABAergic synapses are often axo-somatic or axo-axonal
axo-somatic synapses control excitability of cell body
axo-axonal synapses at the axon initial segment influence signal integration
What is GABAergic output from the cerebellum?
Purkinje cells are large GABAergic projection neurons of the cerebellum: provide the sole output of motor coordination from the cerebellar cortex
Purkinje cells are under inhibitory control from GABAergic interneurons: basket cells from axo-axonal synapses at the axon initial segment, stellate cells form axo-dendritic synapses
degeneration of Purkinje neurons is termed Holmes cerebellar degeneration: impaired fine hand movement, speech deficits, tremors, and ataxia while walking
What is the GABAergic control of motor initiation?
medium spiny neurons comprise 90-95% of the neurons in the striatum: inputs from neocortex (all except visual and auditory), outputs to globus pallidus and substantia nigra
involved in two pathways that control inhibition of motor activity in the basal ganglia
direct pathway: excitatory input from cortex causes excitation of upper motor neurons in motor cortex
indirect pathway: excitatory input from cortex causes inhibition of upper motor neurons in motor cortex
What is the direct pathway of motor initiation?
excitatory input from cortex (glutamatergic) to medium spiny neurons (MS) in striatum
inhibitory output from medium spiny neurons to the internal globus pallidus & substantia nigra pars reticula (SNpr)
GABAergic MSN inhibits tonic inhibitory output from globus pallidus –> ventral thalamus (VTh) and form SNpr –> superior colliculus
disinhibits outputs
VTh: excitatory projections to upper motor neurons of cortex
superior colliculus: controlling eye saccades
What is the indirect pathway of motor initiation?
medium spiney neurons project to the external globus pallidus which forms a loop with the subthalamic nuclei
subthalamic nuclei (STN) has excitatory glutamatergic projections to the internal globus pallidus
indirect pathway activation leads to disinhibition of STN projections and this inhibition of motor output (dis-disinhibitory pathway)
What is the dopaminergic balance between the direct and indirect pathways of motor initiation?
dopamine plays a gating role and balances activity between the direct and indirect pathways
activation of nigrostriatal dopamine pathways promotes the direct pathway (D1 - excitatory) over the indirect pathway (D2 - inhibitory)
in Parkinson’s the loss of dopaminergic projections shifts activity to the indirect pathway
What is the cholinergic balance between the direct and indirect pathways of motor initiation?
cholinergic interneurons in the striatum receive excitatory inputs from the cortex
cholinergic interneurons act directly on the direct pathway
M4AChR antagonists and AChE inhibitors are useful therapeutics in early Parkinson’s as they compensate for decreased dopaminergic input
What are ionotropic (GABAA) receptors?
classic ligand gated ion channel permeable to Cl-
5 subunits form the channel pore
originally characterized by sensitivity to bicucculine (comp. antagonist)
What are metabotropic (GABAB) receptors?
G-protein coupled receptors
Gi - inhibits adenylate cyclase (decreased cAMP)
G-beta-gamma: opens G-protein coupled K+ channel (GIRK)
originally characterized by sensitivity to baclofen (specific agonist)
What are the characteristics of GABAA?
pentameric channel (5 subunits) through combination of 19 different genes
normal channel form is at least 1 each of alpha and beta: usually 2 alpha, 2 beta, and 1 of something else
special case is GABAAP which only forms homopentameric channels with itself
What are the GABAA receptor binding sites?
GABAA has 4 binding sites for endogenous and exogenous ligands
GABA site: binds two molecules of GABA at the interface between alpha and beta subunits
benzodiazepine site: binds benzodiazepines (tranquilizers) as positive allosteric modulators
barbiturate site: binds barbiturates (sedative & anxiolytics) as positive or negative allosteric modulators
picrotoxin is a non-competitive channel blocker
What binds to the non-competitive sites of the GABAA receptor?
pentylenetetrazol binds in the pore at the same site as picrotoxin and was used as a convulsant for depression therapy (discontinued due to high risks of spontaneous seizures, widely replaced with electroconvulsive therapy in 1939)
GABA site: competitive antagonist is bicucculine - potent convulsant, classic agonist if muscimol
What is Amanita muscaria (fly agaric)?
source of the muscarinic AChR agonist muscarine
source of the GABAA agonist muscimol
potent hallucination: induces macroscopia, perception of objects being larger than they are
consumption of fly agaric has serious peripheral side-effects due to muscarinic cholinergic effects at NMJ and parasympathetic effects
Gaboxidol is a synthetic version of muscimol with reduced psychotropic effects: anxiolytic and analgesic, investigated for insomnia treatment
What are benzodiazepines?
sedative-hypnotic, anxiolytic
Diazepam (Valium) one of the best known
better safety margin than barbiturates
binding causes increased probability of pore opening
high risks of drug interactions at the GABAA receptor
orphan receptor site: endogenous ligand not known
What are barbiturates?
sedative-hypnotic, anaesthetic
Phenobarbitol best known
narrow safety margin: high potential for abuse, high risk of overdose
binding prolongs open time of Cl- pore
used in physician-assisted suicide and euthanasia
sodium amytal (amobarbital) is a barbiturate known as a “truth serum”: helps to circumvent inhibitions
How does ethanol interact with the GABAA receptor?
ethanol is a potent positive allosteric modulator of GABAA binding to a site on the transmembrane surface of the delta-subunit
ethanol exerts many of it’s sedative, euphoric, and addictive effects through modulation of GABAA
ethanol binds GABAA with very high affinity - binding even at doses that would be considered moderate, social levels
How does propofol interact with the GABAA receptor?
propofol is a potent anaesthetic that interacts with the transmembrane surface of the beta-subunit of GABAA
positive allosteric modulator that increases channel open time
