inhibitory transmission Flashcards
what is GABAaR
a transmitter gated anion channel which consists of 5 transmembrane subunits
what is GABAbR
a G-protein coupled receptor consisting of 2 subunits
what is the major inhibitory receptor in the mamallian brain
GABAaR
what is fast inhibition in the spinal cord mediated by
GABAaRs and glycine receptors
what are GABAaR inhibitors
proconvulsant and anxiogenic
what are drugs that enhance GABAaR function called
positive allosteric modulators (PAMs)
what is an example of a PAM
diazepam
what is the function of PAMs
anticonvulsant, anxiolytic, sedative and analgesic
do PAMs work in the absence of GABAaR
no
how do PAMs work
they enhance the effects of GABA whilst binding to a different part of the pentamer
describe the GABAbR
a heterodimer with GABAb1 providing the GABA binding domain and GABAb2 the G-protein coupling to Gai and Gao
what is baclofen
a slective GABAbR agonist used clinically to treat certain types of spacifity (muscle stiffness) reesultant from multiple sclerosis and spinal cord injuries
it is a skeletal muscle relaxant which acts on the spinal cord
how does GABA transmission work
a-ketoglutarate is made into glutamate by GATA-T
glutamate is made into GABA via GAD
GABA is backagaed by VGAT and then released into the synapse via exocytosis
the GABA attaches to GABAaR to cause hyperpolarisation
what is the affinity of extra-synaptic receptors for GABA
very high affinity - constantly opening and closing i response to very small concs of GABA
GABARs that are directly on the post-synaptic membrane have…
low affinity for GABA
what is phasic inhibition
fast
what is tonic injibition
slow
what is feed-forward inhibition
Involves a bi-synaptic inhibitory response. (GABA) arrives only 1-5 msec after the monosynaptic excitatory (glutamate) input, thereby limiting the time window for the summation of excitatory inputs to generate an action potential
what does activation of glutamate-gated cation conducting channels produce
EPSP
what does activation of a GABA-gated anion conducting channel produce
IPSP (inhibitory postsynaptic potential)
how does feed-back inhibition work
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 tge Gi a subunit do in a GABAb receptor
inhibits adenylate cyclase (AC) activity to decrease cAMP levels
what does postsynaptic GABAb activation cause
causes the Gi bY complex to open a K+channel causing hyperpolarisation.
what does pre-synaptic GABAb activation cause
the Go BY complex to decrease the probability of voltage-gated Ca2+channels opening, thereby decreasing the quantal release of neurotransmitter
what is mediated by presynaptic GABAb receptors
auto-inhibition of GABA release
what does GABA act post-synaptically to do
activate chloride-conducting GABAaRs to produce a IPSP
also, activate GABABRs (viaGo) to decrease the probability of Ca channel opening and consequently decrease GABA release upon a second stimulus
also, activates postsynaptic G-protein coupled GABABRs (Gi). Activation of GABABRs causes the opening of a potassium channel leading to a further, but prolonged hyperpolarisation i.e. a prolonged IPSP
PAMs are…
anxiolytic, anticonvulsant, analgesic, amnestic, sedative/hypnotic, general anaesthetic
drugs that inhibit GABAaR function are…
pro-convulsant (in high doses) and anxiogenic
how do benzodiazapines effect channel opening
increase the probability of channel openings
what do barbiturates promote
channel open states of long duration
what do barbiturates do at high concentration
directly activate the receptor
what induces anaesthetic (unconscious) states at high doses
barbiturates, propofol and etomidate
in the human brain, how many different GABAaR subunits are there
19
which GABAaR subunits does diazepam enhance the function of
a1, a2, a3 and a5
which GABAaR subunits does diazepam not enhance the function of
a4 and a6
why does diazepam only enhance the function of some subunits
because it can only enhance function in the presence of a H residue at position 101
where do general anaesthetics work
non-specifically on the membrane
what effect does binding on the a1 subunit of the GABAaR have
sedation
what effect does binding on the a2, a3 subunit of the GABAaR have
anxiolytic/analgesic
what effect does binding on the a5 subunit of the GABAaR have
cognition (alzheimers)
what effect does binding on the b3 subunit of the GABAaR have
immobiloty/anaesthesia
what effect does binding on the b2 subunit of the GABAaR have
sedation/anaesthesia
how quickly does induction of general anaesthethia by progesterone metabolites work
rapidly
how do progesterone metabolites have such a rapid effect on brain activity
non-genomic effect the steroid
where do alcohol, antidepressants and GHB exert their effects
through neurosteroids
what do neurosteriods do
fine tune neural inhibition
what are strychnine-sensitive glycine receptors
anion-selective transmitter-gated ion channels
what do strychnine-sensitive glycine receptors regulate
respiratory rhythms, motoe control, muscle tone, sensory and pain processing
what is the strychnine-sensitive glycine receptor activated by
glycine
taurine
strychnine
what causes hyperekplexia
mutations of the glycine receptor
what are the most frequent mutations in the glycine receptor
R271L/Q
what do mutations of the glycine receptor do
decrease both glycine sensitivity and the single channel conductance
