INHIBITORY TRANSMISSION Flashcards
GABA influences neuronal signalling via activation of what
GABAa and GABAb receptors
The major inhibitory receptor in the mammalian brain is what
GABAa receptor
In the spinal cord fast inhibition is mediated by what
GABAaRs and glycine receptors
GABAaR inhibitors are what
proconvulsant and anxiogenic
Drugs that enhance GABAaR functions are called what
Positive allosteric modulators- PAMs (diazepam)
They are anticonvulsant, anxiolytic, sedative and analgesic
Describe the structure of GABAbR
A heterodimer with GABAB1 providing the GABA binding domain and GABAB2 the G protein coupling to Gai and Gao
What is Baclofen
A skeletal muscle relaxant acting on the spinal cord
A seelctive GABABR angonist used clinically to treat certain types of spasticity (muscle stiffness) resultant from multiple sceloris and spinal cord injuries
What is GABA-T
Gaba-transaminase
Describe the process of inhibitory GABA-ergic transmission
a-ketoglutarate works with GABA-T to turn into glutamate where then GAD (Glutamic acid decarboxylase) turns this into GABA
This GABA then goes through endocytosis and is pacled into vesicles where it goes through exocytosis and exits the synapse through to the GABAaR receptor
What is phasic inhibition
Phasic inhibition is mediated by the fast activation of synaptic GABAARs from synaptically released GABA
What is tonic inhibition
Tonic inhibition depends on the sustained activation of peri- and extrasynaptic GABAARs by ambient GABA in the extracellular space.
What is feed forward inhibition
Involves a bi-synaptic inhibitory response. GABA arrives only 1-5msec after the monosynaptic excitory glutamate input, therby inhibiting the time window for summation of excitory inputs to generate an action potential
Activation of glutamate-gated cation conducting channels produce an excitory postsynaptic potential (EPSP)
Activation of GABA- gated anion conducting channels produce an inhibitory postsynaptic potential (IPSP)
What is feedback inihibition
The firing of the pyramidal neuron activates an inhibitory interneuron, which in turn inhibits the pyramidal neuron. once the inhibition decays, the pyramidal neuron can fire again
What does the Gi alpha subunit inhibit
adenylate cyclase activity to decrease cAMP levels
Post synaptic GABAb activation causes the Gi beta gamma complex to open what?
Open the K+ channel causing hyperpolarisation
Pre-synaptic GABAb activation causes the Go beta gamma complex to decrease the probabiltiy of volatge gated Ca2+ channels opening, thereby decreasign what
The quantal release of neurotransmitter
Auto-inhibition of GABA release mediated by what
GABAb receptors
Explain the auto-inhibtion of GABA release mediated by presynaptic GABAb receptors
- GABA acts post-synaptically to activate chloride conducting GABAaRs to produce an IPSP
- GABA also acts pre-synaptically to activate GABAbRs (via GO) to decrease the probability of Ca channel opening and consequently decrease GABA release upon a second stimulus
Explain the process of activation of post-synaptic GABAb receptors opens K+ channels to prolong post-synaptic inhibtion mediated by GABA
- GABA acts post-synaptically to activate chloride-conducting GABAaRs causing an IPSP
- Additionally GABA activates postsynaptic G-protein coupled GABAbRs (Gi). Activation of GABAbRs causes the opening of a potassium channel leading to a further, but prolonged hyper polarisation- prolonged IPSP
What are drugs that enhance GABAaR function
PAMs
- Anxiolytic, anticonvulsant, analgesic, amnestic
- Sedative/hypnotic- general anaesthetic
What are drugs that inhibit GABAaR function
Pro-convulsant, anxiogenic
What do barbituates and benzodiazepines do to GABAaR function
Bind to different sites and enhance their function by different mechanisms
What do benzodiazepines do to the channel opening
Increase the probability of the channel opening
What do barbituates do to the channel
Promote channel open for long states of duration
At higher concentrations directly activate the receptor
At high doses, propofol and etomidate induce a anaesthetic (unconcious state) whereas benzodiazepines do not
Diazepam enhances the function of a1, a2, a3 and a5By2-GABAaRs but not a4 or a6 GABAaRS. Why is this?
- Alpha 1,2,3 and 5 subunits have a H residue at position 101 whereas both a4 and a 6 subunits have R residues at this position
2.Mutation of a6 R101 to H produces a diazepam sensitive receptor, whereas mutation of a1H101 to R blocks diazepam sensitivity
What is etomidate?
A general anaesthetic IV
Selective for GABAaRs incorporating B2 or B3 subunits
The anxiolytic effect of diazepam is mediated by what?
a2-GABAaRs
What drug is used for treatment of post-partum depression
Brexanolone
Post pd is associated with reduced expression of GABAaRs
What are strychnine-sensitive glycine receptors
Anion selective transmitter gated ion channel, closely related to the GABAaR family
More restricted expression of the CNS - spinal cord, brain stem and a few selected brain regions (cerebellum, dorsal raphe)
What is the function of strychnine-senstive glycine receptors
Regulate important physiological functions including respiratpry rhythms, motor control, muscle tone, sensory pain and processing
What are agonist for the Strychnine-sensitive glycine receptor
Propofol, Glycine Taurin Strychnine and volatile anaesthetics and alcohols eg isoflurane and ethanol
Where does strychnine originate from
Obtained from poisonous nuts of the strychnine tree
A potent competitve antagonist
Enhances the perception of pain
Causes convulsions
What is hyperekplexia (human startle disease)
Rare neurological disorder characterised by neonatal hypertonia (spasticity) exaggerated startle response to unexpected stimuli (touch and sound) and variable incidence of apnoea, intellectual disability and delays in speech acquisition
How is hyperekplexia (human startle disease) treated
Treated with clonazepam (a benzodiazepine- GABAaRs PAM)
What mutation causes hyperekplexia?
mutation of the glycine receptor
R271L/Q most frequent mutations. They decrease both glycine sensitivity and the single channel conductance (y)
