GABA Receptors and Subunits Info

GABA(A) Receptors and Subunits

The GABA(A) receptor complex has many different subunits, which in turn have isoforms or otherwise known as subtypes (A1-6, B1-4, Y1-3, δ, ε, θ, and P1-2).

Of those subtypes only three of the subunits (Alpha, Beta, Gamma) are BZD sensitive.

The A (Alpha) subunit has 6 subtypes but only a1, a2, a3, and a5 are BZD sensitive.

The B (Beta) subunit has 4 subtypes, but only b3 subtype is BZD sensitive.

The Y (Gamma) subunit has 3 subtypes, but only y2 subtype is BZD sensitive.

Subunits from only one class (A) or two classes (A and B) can form functional GABA receprots under experimental conditions, but subunits from three classes (A, B, and Y) are needed for full receptor function. Threse three subunits also compose most of the GABA(A) receptoris in our brains.

The Alpha (A) subunit

The most important subunit is "Alpha" and it's subtype isoforms (a1,2,3, and 5). The alpha subunit is responsible for mediating most of the effects of the benzos. All benzos bind to this subunit but they also all have different affinitie levels to the different subtypes.

A1 subtype: Sedation, Respiratory depression, Sleep, Ataxia, Motor-impairment, Amnesia, Anti-convulsive, and Reinforcing Behavior.

A2 subtype: Anxiolysis, Disinhibition

A3 subtype: Anxiolysis, Anti-Convulsive, Muscle Relaxation

A5 subtype: Learning and Memory, Amnesia, Minor Sedation

A3 & A5 subtype: Sensorimotor information processing

The Beta (B) and Gamma (Y) subunits

Y2 subtype: Physical dependence, respiratory Depression

B3 subtype: Anti-Convulsive, Minor Sedation, Muscle Relaxation, various other reactions related to respiration. This subtype is a barbiturate receptor.

Benzos affinity to the GABA(A) receptors

High A1 affinity: Midazolam, Triazolam, Flunitrazepam, Temazepam, Lormetazepam, Nitrazepam, Brotizolam, Nimetazepam, Loprazolam, and Flutoprazepam.

Low to Moderate A1 affinity: Wide range of 1,4 benzodiazepines including Diazepam, Estazolam, Flurazepam, Oxazepam, Lorazepam, Alprazolam, Bromazepam, Camazepam, Quazepam (highly selective affinity), Clonazepam, Medazepam, Nordazepam, Chlordiazepoxide (very weak affinity), Clorazepate, and most other benzo as all benzos are A1 agonists with varying degrees of affinity levels. Also included here are the Nonbenzodiazepine "z-drugs" such as Zolpidem, Zaleplon, Zopiclone, and Eszopiclone which are all highly selective of the A1 subtype receptor but with only weak to moderate affinity.

High A2 affinity: Diazepam, Clonazepam, Bromazepam, Lorazepam, Alprazolam, Camazepam, Nitrazepam, Loprazolam, Lormetazepam, and Flutoprazepam.

Moderate A2 affinity: Oxazepam, Prazepam, Phenazepam, Temazepam, Flunitrazepam, Halazepam, Midazolam, and other less commonly known benzos.

Weak A2 affinity: Triazolam, Chlordiazepoxide (stronger affinity for A3), Brotizolam, Quazepam, Tetrazepam (stronger affinity for A3), and a few others.

High A3 affinity: Diazepam, Clonazepam, Temazepam, Lorazepam, Tetrazepam, Flunitrazepam, Nimetazepam, Phenazepam, and Bromazepam.

Moderate A3 affinity: Alprazolam, Adinazolam, Estazolam, Chlordiazepoxide, Clorazepate, and Flurazepam.

High Y2 affinity (These benzos are the most physically addictive): Temazepam, Brotizolam, Triazolam, Alprazolam, Lorazepam, Loprazolam, Midazolam, Flunitrazepam, Clonazepam, Lormetazepam, Flutoprazepam, Nitrazepam, Nimetazepam, and Estazolam

Low to moderate Y2 affinity: Diazepam, Chlordiazepoxide, Oxazepam, and most other benzos.

High B3 affinity: Mostly Hypnotics (Nitrazepam, Temazepam, Triazolam, etc)

Low to moderate B3 affinity: Diazepam, Alprazolam, most other benzos.

Source: Current Medicinal Chemistry, Volume 14, Number 26, November 2007 , pp. 2755-2775(21)