INHIBITORY TRANSMISSION

Question 1

GABA influences neuronal signalling via activation of what

Answer 1

GABAa and GABAb receptors

Question 2

The major inhibitory receptor in the mammalian brain is what

Answer 2

GABAa receptor

Question 3

In the spinal cord fast inhibition is mediated by what

Answer 3

GABAaRs and glycine receptors

Question 4

GABAaR inhibitors are what

Answer 4

proconvulsant and anxiogenic

Question 5

Drugs that enhance GABAaR functions are called what

Answer 5

Positive allosteric modulators- PAMs (diazepam)
They are anticonvulsant, anxiolytic, sedative and analgesic

Question 6

Describe the structure of GABAbR

Answer 6

A heterodimer with GABAB1 providing the GABA binding domain and GABAB2 the G protein coupling to Gai and Gao

Question 7

What is Baclofen

Answer 7

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

Question 8

What is GABA-T

Answer 8

Gaba-transaminase

Question 9

Describe the process of inhibitory GABA-ergic transmission

Answer 9

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

Question 10

What is phasic inhibition

Answer 10

Phasic inhibition is mediated by the fast activation of synaptic GABAARs from synaptically released GABA

Question 11

What is tonic inhibition

Answer 11

Tonic inhibition depends on the sustained activation of peri- and extrasynaptic GABAARs by ambient GABA in the extracellular space.

Question 12

What is feed forward inhibition

Answer 12

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)

Question 13

What is feedback inihibition

Answer 13

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

Question 14

What does the Gi alpha subunit inhibit

Answer 14

adenylate cyclase activity to decrease cAMP levels

Question 15

Post synaptic GABAb activation causes the Gi beta gamma complex to open what?

Answer 15

Open the K+ channel causing hyperpolarisation

Question 16

Pre-synaptic GABAb activation causes the Go beta gamma complex to decrease the probabiltiy of volatge gated Ca2+ channels opening, thereby decreasign what

Answer 16

The quantal release of neurotransmitter

Question 17

Auto-inhibition of GABA release mediated by what

Answer 17

GABAb receptors

Question 18

Explain the auto-inhibtion of GABA release mediated by presynaptic GABAb receptors

Answer 18

1. GABA acts post-synaptically to activate chloride conducting GABAaRs to produce an IPSP
2. 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

Question 19

Explain the process of activation of post-synaptic GABAb receptors opens K+ channels to prolong post-synaptic inhibtion mediated by GABA

Answer 19

1. GABA acts post-synaptically to activate chloride-conducting GABAaRs causing an IPSP
2. 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

Question 20

What are drugs that enhance GABAaR function

Answer 20

PAMs
- Anxiolytic, anticonvulsant, analgesic, amnestic
- Sedative/hypnotic- general anaesthetic

Question 21

What are drugs that inhibit GABAaR function

Answer 21

Pro-convulsant, anxiogenic

Question 22

What do barbituates and benzodiazepines do to GABAaR function

Answer 22

Bind to different sites and enhance their function by different mechanisms

Question 23

What do benzodiazepines do to the channel opening

Answer 23

Increase the probability of the channel opening

Question 24

What do barbituates do to the channel

Answer 24

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

Question 25

Diazepam enhances the function of a1, a2, a3 and a5By2-GABAaRs but not a4 or a6 GABAaRS. Why is this?

Answer 25

1. 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

Question 26

What is etomidate?

Answer 26

A general anaesthetic IV Selective for GABAaRs incorporating B2 or B3 subunits

Question 27

The anxiolytic effect of diazepam is mediated by what?

Answer 27

a2-GABAaRs

Question 28

What drug is used for treatment of post-partum depression

Answer 28

Brexanolone Post pd is associated with reduced expression of GABAaRs

Question 29

What are strychnine-sensitive glycine receptors

Answer 29

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)

Question 30

What is the function of strychnine-senstive glycine receptors

Answer 30

Regulate important physiological functions including respiratpry rhythms, motor control, muscle tone, sensory pain and processing

Question 31

What are agonist for the Strychnine-sensitive glycine receptor

Answer 31

Propofol, Glycine Taurin Strychnine and volatile anaesthetics and alcohols eg isoflurane and ethanol

Question 32

Where does strychnine originate from

Answer 32

Obtained from poisonous nuts of the strychnine tree A potent competitve antagonist Enhances the perception of pain Causes convulsions

Question 33

What is hyperekplexia (human startle disease)

Answer 33

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

Question 34

How is hyperekplexia (human startle disease) treated

Answer 34

Treated with clonazepam (a benzodiazepine- GABAaRs PAM)

Question 35

What mutation causes hyperekplexia?

Answer 35

mutation of the glycine receptor R271L/Q most frequent mutations. They decrease both glycine sensitivity and the single channel conductance (y)