Name the 7 therapeutic target of the GABAA receptor?
1. Volatile anaesthetics. 2. Benzodiazepines. 3. Propofol. 4. Barbiturates. 5. Steroids. 6. GABA. 7. Etomidate
Name the 6 drugs that enhance GABAA receptor function?
1. Anxiolytics. 2. Anticonvulsant. 3. Analgesic 4. Amnestic 5. Sedative 6. Anaesthetics
Positive allosteric modulators. Binds to the receptor and enhances the response.
Define the function of barbiturates and benzodiazepines?
Enhances GABAA receptor function.
How does barbiturates enhance GABAA receptor function?
Promotes open states of long duration and when at a high conc can activate the receptor.
How does benzodiazepines enhance GABAA receptor function?
Increase the probability of the channel opening.
What two molecules block the GABA receptor from functioning?
Picrotoxin and bicuculine.
What subunits make up GABAA receptor?
2x alpha 2 x beta 1 x gamma
Where does the GABA bind to the GABAA receptor?>
Between the alpha and beta subunits.
Where does the benzodiazepines bind to in the GABAA receptor?
Between the gamma and alpha subunits.
How do you get so many different types of GABAA receptors?
Lots of different subunits- depending on the function of the GABAA receptor.
What does the alpha subunit contribute to when looking at the interface?
The negative (secondary) interface
What does the beta subunit contribute to when thinking of interface?
Contributes to the positive (primary) interface.
How many Transmembrane domains does the GABAA receptor have?
How many subunits per transmembrane domain does the GABAA receptor have?
Alpha 1 binding sites properties of binding benzodiazepine?
Sensitive to classical benzodiazepines such as diazepam.
Alpha 6 binding site properties of binding benzodiazepines?
Insensitive to classical benzodiazepines
What is used to distinguish between GABAA receptor subtypes?
Distinct physiological and pharmacological properties. Distinct CNS distribution Mediate different behaviours.
What are the 4 behaviours that are induced by benzodiazepines?
1. Sedation 2. Anxiolytic 3. Analgesic 4. Cognition
What subtype of GABAA links with each behaviour it induces?
Alpha 1: sedation Alpha 2/3: anxiolytic/analgesic Beta3: Immobility/anaesthesia Beta 2: sedation/anaesthesia Alpha 5: Cognition
Name the 3 therapeutic targets of the strychnine-sensitive glycine receptor?
1. Volatile anaesthetics and alcohols. 2. Propofol 3. Glycine, taurine and strychnine (Agonist)
What is the strychnine?
A potent competitive antagonist. Enhances the perception of pain and causes convulsions.
What are the properties of the strychnin-sensitive glycine receptor?
Chloride channel. Anion-selective transmitter-gated ion channels. Cys loop
Where is the glycine strychnine-sensitive glycine receptor located?
More restricted expression in the CNS.
Name the 4 functions of the strychnine-sensitive glycine receptor?
1. Respiratory rhythms 2. Motor control. 3. Muscle tone. 4. Sensory and pain processing.
How many subunits is the glycine receptor made up of?
5 subunits Either 5 alpha or 2 alpha& 3 beta.
Where does the glycine bind to on the glycine receptor?
Gamma1-3 binds between the alpha 1 subunits. Other glycine binds between alpha 1 and beta.
GABA- transaminase. Converts alpha-ketoglutarate into glutamate.
What blocks the action of GABA-T?
Glutamic acid decarboxylase. Converts glutamate into GABA.
Define "GAT 1-3"?
GABA transporter. Transports GABA back into the presynaptic membrane to repackage them.
What blocks the action of GAT 1-3?
Blocked by tiagabine
Vesicular GABA amino acid transporter. Transports GABA into the vesicle.
What is postsynpatic GABAA and B receptor role in the inhibitory GABA transmission?
GABAB is used to transport chlorine across the membrane. GABAA is used to pick up the GABA receptor to cause the depolarisation.
Describe the inhibitory transmission process?
Alpha-ketoglutarate is converted to glutamate and then to GABA. This GABA is then packaged into vesicles and the vesicles themselves are excreted from the membrane and into the cleft. This release of GABA is detected by the GABAA receptor and binds to it causing chlorine to enter.
What is the presynaptic GABAB receptor role in the inhibitory GABA transmission?
Used to uptake chlorine into the presynaptic membrane.
Describe the inhibitory glycinergic transmission process>
Glycine is transported into the vesicle by a H/glycine exchanger. This vesicle undergoes exocytosis into the cleft and taken up by glycine receptors- causing a chlorine intake. The extra glycine is taken up by GlyT1 (on the astrocyte) and GlyT2 (on the presynaptic membrane).
Name the exchanger that is used to transport glycine to a vesicle in the inhibitory glycinergic transmission process?
Name the glycine receptor found on the astrocyte?
GlyT1 astrocytic glycine transporter.
Name the glycine receptor found on the presynaptic membrane?
GlyT2 neuronal glycine transporter.
What type of receptors kynurenic acid block?
What type of channels are blocked by TTX?
Describe the properties of the phasic inhibition?
Release of a single packet of vesicle stimulating the chloride receptors on the postsynaptic membrane to open. Causes the depolarisation.
Describe the properties of the tonic inhibition?
Activation of low levels of GABA. Chlorine receptors pick up the GABA and open them.
What is the effect of neurosteroids on the inhibition response?
Prolongs the affect of the inhibition by keeping the cell in the inhibitory state for a longer period of time.
Name the two main modes of inhibition?
Phasic and tonic inhibition
What binding domain does a heterodimer with GABAB1 provide?
The GABA binding domain
What type of coupling is provided by the GABAB2?
G-rptoein coupling to Gi and Go.
What does the Gi alpha subunit do?
Inhibits the adenylate cyclase activity to decrease cAMP.
What does the postsynpatic GABAB activation cause?
The Gi beta:gamma complex to open a potassium channel. Causing a hyperpolarisation.
What does the presynaptic GABAB activation cause?
The Go beta/gamma complex to decrease the probability of the voltage-gated calcium channels to open. Thus decreasing the quantal release of neurotransmitter.
What does baclofen do?
It is a GABAB agonist. Used to treat spasticity.
Describe the auto-inhibition mediated by presynaptic hippocampal GABAB receptors?
1. GABA acts post-synaptically to activate chloride-conducting GABAA receptors to produce IPSP. 2. GABA also acts pre-synaptically to activate GABAB receptors to decrease the probability of calcium channels opening. Thus decreasing GABA release upon a second stimulus.
Define the term "IPSP"?
Inhibitory postsynpatic potential.
Describe the activation process of post-synaptic GABAB receptors to open potassium channels?
This needs to be done to prolong the post-synpatic inhibition mediated by GABA. 1. GABA acts post-synaptically to activate chloride-conducting GABAA receptors to produce IPSP. 2. Additionally, GABA activates postsynaptic G-protein coupled GABAB receptors. Activation of these receptors causes the opening of potassium channels leading to prolonged hyper polarisation (or a prolonged IPSP).
Describe the term "feed-forward inhibition"?
Bi-synpatic inhibitory response (gaba) arrives straight after the monosynaptic excitatory (glutamate) input. Thereby, limiting the time window for the summation of excitatory inputs to cause an AP.
Name the 3 ways in which the GABA interneurones differ between types?
1. Firing rate. 2. Part of the principal neurone they innervate. 3. Subtype of synaptic GABAA receptor they activate.
Define the term "CCK"?
Cholecystokinin interneurons. Asynchronous release of GABA. Express CB2 receptors.
Define the term "PV"?
Parvalbumin fast spiking interneurones. Synchronous GABA release. Express mu (u) opioid receptors.
What differs between activation of alpha 1 GABAA receptors and alpha 2 GABAA receptors?
Alpha 1 produces briefer IPSCs than Alpha 2.
The physiological levels of GABA during pregnancy?
Levels are high during giving birth but drop rapidly after birth. Causing post-natal depression
How do other cells influence the GABA response?
Local neurosteroid release influences the GABAA receptors affecting the response. eg. glial cell.
What is glycine?
Inhibitory neurotransmitter in the CNS