GABA systems Flashcards
GABA ?
Gaba , gamma amino butyric acid is an amino acid that is synthesised from amino acid glutamate by the enzyme glutamate decarboxylation. Identified in brain tissue in 1950 by Robert and Frankel , it is found exclusively in brain tissue as an inhibitory neurotransmitter and found in high concentrations in CNS tissues when compared to other compounds such as noradrenaline and serotonin it is in nanomolar. It is measured in mmole/ml (c.f. monoamines = nmole/ml). It is also found within CNS tissue in striatum, substantia niagra, hippocampus, globus pallidus and many other areas .
distribution of GABA ?
When a cross section through a brain occurs it shows anatomical areas of the brain and shows a wide distribution of neurons containing GABA in CNS. Almost all short neurones exist within regions instead of between regions. Only one region that contains GABA between neurons and this is substantia nigra.
release of GABA ?
GABA takes part in the neurotransmitter behaviour and is synthesised in neurones and stored in nerve terminals in synaptic vesicles. It is released from these vesicles in a calcium dependent manner to act on post synaptic receptors. Synaptic removal occurs after effects have occurred by reuptake to nerve terminals and nearby glial cells . GABA transporter (GAT) terminates synaptic action, there are four variants: GAT1, GAT2, GAT3 and BGT1 . It is a sodium ion symporter that uses energy as GABA is moving up it’s concentration gradient while sodium ions move down their concentration gradien
catabolism of GABA ?
Catabolism, once GABA has been taken up within both neuronal and non-neuronal tissue it is broken down and converted to succinate by GABA transaminase (GABA-T) . GABA + 2-oxyglutarate à succinate semialdehyde + glutamate. GABA + glyoxylate à succinate semialdehyde + glycine
binding of GABA described as ?
GABA binds to CNS tissue, the binding of GABA to brain is saturable and specific
2 main classes of binding sites ?
There are two main classes of binding sites : GABA receptors whose binding is not sodium-dependent and GABA uptake site which greatly outnumber GABA receptor sites , there are neuronal and non-neuronal , the binding is sodium-dependent ( larger number) but not binding to receptor, instead binds to transporter.
GABA A ?`
GABAA is an ionotropic ligand gated chlorine ion channel. GABAA receptors are mainly located post synaptically. The GABAA receptors are pentamers composed of different subunits, each pentamer receptor contains a mix of alpha and beta subunits , however the most common confirmation is 2 alpha , two beta and one gamma subunit arranged in a circle sequence which is similar to the nicotinic receptor structure
GABA A sensitive to ?
GABAA is sensitive to the antagonist buculline and baclofen insensitive , activation of the chloride ion channel allows the movement of chloride ions across the membrane of the cell which leads to stabilisation of the cell and renders it unexcitable. This is why it is termed an inhibitory neurotransmitter. Agonists that are potent for GABAA include isoguvaine which is competitive , picrotoxin which is non competitive , gaboxadol is a moderately potent
GABA A binding sites and BDZ ?
Within the GABAA binding sites, there are 2 interfaces that lie between the alpha and beta subunits , only when GABA is bound to both of these sites will chloride ions flow through. There is also a benzodiazepine binding site which lies between the gamma and alpha subunits.
GABA rho ?
GABArho receptors are also commonly called the GABAC receptor and they are located in the retinal bipolar cells , it shares structural similarities to the GABA receptor and it composed of a 5 subunit ligand gated ion channel. It is composed solely of three Rho (p) subunit varieties. It has different pharmacological pharmacology to the GABA receptors as they are insensitive to bicuculine , barbiturates , benzodiazepines and baclofen. They are sensitive to CACA, TPMPA, picrotoxin.
GABA B ?
GABAB is a metabotropic G protein coupled receptor that is coupled to Gi/o which inhibits the voltage gated calcium channels , resulting in the opening of potassium channels which inhibit the effector enzyme adenyl cyclase ,therefore reducing transmitter release. The receptor is a heterodimer composed of 2 7TM receptors that share similarity in structure to the muscarinic receptors.
GABA B sensitive to ?
The GABAB receptors are sensitive to the agonist baclofen and insensitive to bicuculline. A potent antagonist for GABAB is 2-hydroxy-S(-) saclofen. There are no known modulators for GABAB receptors.
celllular effects of GABA on spinal cord of CNS ?
GABA is inhibitory on the spinal cord of the CNS presynapticlly, it reduces the transmitter release from the terminals of the primary afferent fibre, the pharmacological effects are distinct from glycine. Bicuculine and picrotoxin will block the inhibitory effects of GABA, while strychnine blocks the effects of glycine.
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GABA effect on post synaptic transmission ?
GABA also has an effect of inhibiting post synaptic transmission, most of the GABA effects are in brain , an increased chloride flux postsynaptic in GABAA causes a decrease in the ability of the cell to fire. As an Example pathways: striatal (caudate putamen) substantia nigra , will inhibit firing of DA neurons .This is a direct and indirect (interneuron) effect , hippocampal and cerebral pyramidal cells as external and recurrent inhibition.
dopaminergic pathway ?
Dopaminergic pathway runs from the substania nigra to the caudate putamen. The GABA is a modulatory neurotransmitter of this pathway. This pathway is important in the control of the motor coordination and motor function. The GABA modulatory pathway runs in the opposite direction from the caudate putamen to the substantia nigra. This is a negative feedback system. If there is a lot of activity in the dopaminergic pathway this leads to an increased activity in the GABAergic pathway. The release of the GABA neurotransmitter will act on the dopaminergic neurons directly or indirectly via an interneuron and this will inhibit the firing from the dopaminergic neurons in the substantia nigra.
