Subtypes of GABAA Receptors

Question 1

What is the GABA(A) receptor

Answer 1

• 5 transmembrane crossing subunits
• an important therapeutic target for benzodiazepines and certain IV anaesthetics
• receptors are designed to relay information rapidly to one another

Question 2

Drugs that enhance GABA(A)R function

Answer 2

anxiolytic, anticolvulsant, analgesic, amnestic, sedative/hypnotic and anaesthetic

Question 3

Positive allosteric modulators (PAMs)

Answer 3

enhance function (e.g. diazepam, flunitrazepam)

Question 4

Negative allosteric modulators (NAMs)

Answer 4

decrease function (antagonists) e.g. DMCM, a beta-carboline that produces anxiogenic effects

Question 5

Benzodiazepine binding site

Answer 5

• interface between alpha and gamma subunit
• for high affinity binding of diazepam, the receptor must contain a gamma subunit (usually gamma2)
• GABA(A)Rs incorporating the gamma2 and alpha1,2,3,5 subunits are diazepam sensitive
• GABA(A)Rs incorporating gamma2 and alpha6 or alpha4 subunits are diazepam insensitive

Question 6

What GABA(A)R composition is benzodiazepine sensitive

Answer 6

alpha1beta1gamma2

Question 7

Why is diazepam insensitive to GABA(A)Rs incorporating gamm2 or alpha4/alpha6 subunits

Answer 7

• H residue at position 101 in alpha 1,2,3,5
• R residue at position 101 in alpha 4,6
• mutation of alpha6 R101 to H101 produces diazepam-sensitive receptor
• mutation of H101 to R101 blocks sensitivity

Question 8

Diazepam in a2H101R mouse

Answer 8

sedative

Question 9

Diazepam in a1H101R mouse

Answer 9

anxiolytic

Question 10

L-838,417 drug

Answer 10

• potentiates GABA acting at alpha2,3,5 but not alpha1 subunit containing receptors
• anxiolytic but not sedative