Case 5

Question 1

What type of receptor is a GABA-A receptor?

Answer 1

Ligand gated ion channel

Question 2

What ion does GABA-A receptor use to bring about its affects?

Answer 2

Chloride Cl-

Question 3

What endogenous ligand acts on GABA-A receptors?

Answer 3

GABA

Question 4

What does GABA do?

Answer 4

Plays a critical role in inhibitory transmission

Question 5

How many subunits make up a GABA-A receptor?

Answer 5

5 subunits

Question 6

What are the 5 subunits that make up the GABA-A receptor?

Answer 6

Could be:
2x alpha 1-6 (α)
2x Beta 1-3 (β)

and either 
1x Gamma (γ) 1-3 or Delta (δ) or Epsilon (ε)  or Pi (π) or Theta (θ) or Rho (ρ)

Question 7

What is the commonest subunit form human of GABA-A receptor?

Answer 7

2x alpha (α)
2X Beta (β)
1x Gamma (γ)

Question 8

What is the form of BDZ-sensitive GABA-A receptor?

Answer 8

2x alpha (α) 1,2,3  (not 4,5,6)*
2x Beta (β)
1x Gamma (γ) 2 or 3  (not 1)*

Question 9

What is the form of BDZ-insensitive GABA-A receptor?

Answer 9

2x alpha (α) 4 or 6  (not 1,2,3,5)*
2x Beta (β)
1x Delta (δ)

Question 10

With regards to the BDZ-sensitive GABA-A receptor: what is it sensitive for?

Answer 10

Benzodiazepines

Question 11

With regards to any GABA-A receptor: where does GABA bind?

Answer 11

between alpha (α) and Beta (β) subunits at the top, and bottom left always.

Question 12

How many GABA molecules can bind to a GABA-A receptor in general?

Answer 12

only 2!

Question 13

With regards to the BDZ-sensitive GABA-A receptor: do BDZ’s bind in the same site as GABA?

Answer 13

NO they do not bind at the GABA binding site.
Therefore are not “direct” antagonists.

They bind to separate allosteric site.
Therefore called positive allosteric molecules (PAM’s)

Question 14

With regards to the BDZ-sensitive GABA-A receptor: How many molecules of BDZ’s can bind?

Answer 14

only 1

Question 15

With regards to the BDZ-sensitive GABA-A receptor: between which subunits do BDZ’s bind?

Answer 15

between alpha (α) 1,2,3 and Gamma (γ) 2 or 3

Question 16

Can BDZ’s elicit their effects without the presence of GABA?

Answer 16

No GABA needs to be present and bound to receptor.

Question 17

Why and how are “Z-drugs” different to BDZ’s. Refer to function on receptor and subunits.

(What are Z drugs selective for - effects, and what are BDZ drugs selective for - effects)

Answer 17

Z-drugs are alpha (α) 1 selective, and therefore hypnotics.

BDZ’s are non alpha (α) selective (i.e. bind to 1,2,3) and so give sedative* effects as well as anxiolytics*.
There are no selective BDZ’s available.

Question 18

With regards to the BDZ-insensitive GABA-A receptor: what is it sensitive for?

Answer 18

Neurosteroids
Alcohol
General Anaesthetics

Question 19

With regards to the BDZ-insensitive GABA-A receptor: where do Alcohol/Neurosteroids/GA’s bind?

Answer 19

between alpha (α) 4 or 6 and Delta (δ)

Question 20

With regards to GABA-A receptors: What does alpha (α) 1 regulate? and what do alpha (α) 2,3 regulate?

i.e. what do they do

Answer 20

alpha (α) 1: regulates sleep

alpha (α) 2 or 3: regulates anxiety

Question 21

What are barbiturates?

Answer 21

They are an old school BDZ.

CNS depressants, sedatives, anxiolytics, muscle relaxants, anticonvulsants, addictive!

Question 22

Where can barbiturates bind to?

Answer 22

They have multiple binding pockets. 
Between Beta (β) and Gamma (γ) 
or alpha (α)/ Gamma (γ)

Question 23

Do barbiturates bind to the same binding sites as BDZ’s?

Answer 23

No, distinct binding sites.

Question 24

Are barbiturates also PAM’s? What is a PAM anyway?

Answer 24

Yes they are PAM’s.

Stands for Positive Allosteric Modulators.

Question 25

How are BDZ’s PAM effects different from barbiturates PAM effect.

i.e. although they both lead to increased CNS inhibition, how is their increased CNS inhibition achieved differently? Describe in terms of channel opening.

Answer 25

BDZ’s increase the opening of the Cl- channel

Barbiturates increase the DURATION of Cl- channel opening.

They both work synergistically (increase frequency)

Question 26

What is the end result of someone overdosing on BDZ’s and barbiturates?

Answer 26

They are lethal in overdose.

Michael Jackson, overdosed in 2009 with benzos and opiates.
Heath Ledger, overdosed in 2008 with benzos and opiates.
Amy Winehouse, overdosed in 2011 with alcohol and benzo drugs.
Whitney Houston, overdosed in 2012 with benzos and multiple prescription drugs