GABA Receptors

Gamma aminobutyric acid (GABA) is the major inhibitory neurotransmitter 20% 0f CNS transmission
GABA A Receptors: Ionotropic (Cl- channel) Pentamer

1. GABA Receptors
Prof. Sawsan Aboul-Fotouh
Department of pharmacology, faculty of Medicine, Ain shams University

2. GABA Receptors
GABA A Receptors GABA B Receptors
Ionotropic (Cl
-
channel)
Pentamer
Metabotropic (Gi-prot.)
Dimer
Also, GABAC Receptor Pentamer of ρ subunits with Cl-channel in the centre(GABAρ)
Gamma aminobutyric acid (GABA) is the major inhibitory neurotransmitter
20% 0f CNS transmission

3. GABAA receptor
Ionotropic (Cl
-
channel)
Pentamer

4. hyperpolarization

6. Benzodiazepines enhance GABA by increasing the frequency
of Cl channel-opening.
Common BZ receptor subtypes in the CNS are designated as BZ
1or BZ
2
depending on whether the binding site includes an α
1or α
2subunit, respectively.
•α
1subunit is associated with sedation/hypnosis. (Z-Hypnotics)
•α
2subunit has greater anxiolyticand muscle relaxation actions

7. Pharmacological Actions of
GABA A Receptors
❑Anxiolysis & Euphoria
❑Sedation & Hypnosis
❑Amnesia
❑Anticonvulsant
❑Muscle relaxation

8. A.FacilitatingGABAAAction(Agonist)(+veAllostericModulators)
1.Barbiturates(GABAmimetic)
2.Benzodiazepines(BZDs)
3.Z-Hypnotics(Zolpidem–Eszopiclone).
4.Alcohols,Acamprosate(Partialagonist)
5.IVAnaesthetics:etomidate,propofol&neuroactivesteroids
6.VolatileAnaesthetics:isofluraneandenflurane
B.AntagonistatBZDsite:Flumazenil(Antidote)
C.InverseagonistsatBZDsite:βcarbolines
Drugs Acting on GABAA Receptors
D. GABA A receptor Blocker Bicuculline & Cl
-
Channel BlockerPicrotoxin, PTZPentylenetetrazole

9. GABA B Receptors
Metabotropic (Gi-prot.)
Coupled to Gi proteins →↓CAMP →
inhibit Ca2+ channels (Presynaptic)
activate K+ channels (Postsynaptic)
Dimer : 2 transmembranedomains: GABAB1 & GABAB2

10. Postsynaptic
GABA
B
Mechanism of GABA B Receptors
GABA
Breceptors: Metabotropic (G-prot.) > in Spinal cord
Presynaptic↓ Ca
2+
influx ↓release of the excitatory transmitter glutamate.
PostsynapticK+ outflux hyperpolarization
Neuronal
Inhibition

11. Drugs acting on GABA B Receptors
Baclofen
-Selective GABA
Bagonist, muscle relaxant
Uses: Treatment of
-Spasticity (e.g. UMNL, CP)
-Skeletal muscle rigidity (e.g. PD, EPS)
Side effect:
-Sedation, weakness, ataxia,
-Can aggravate absence seizures (not used in epilepsy) “Epileptogenesis”

12. GABA A GABA B
Type Ionotropic (Cl-Channel) Metabotropic (Gi-prot.)
Structure Pentamer (2α, 2β, 1γ) Dimer (B1&B2)
Location Widespread; (mainly)
Post-synaptic in CNS
Widespread;
Pre-& Post-synaptic In CNS
(>spinal cord)
MOA Post-synaptic inhibition by -
↑ Cl-influx
Pre-synapticinhibition by –
↓ Ca2+ entry
Post-synaptic inhibition by –
↑ K+ permeability
-Endogenous agonist
-Drugs acting e.g.
GABA
Barbiturates, BZD, Z-Hypnotics
Anesthetics (IV, Volatile…)
GABA
-Baclofen
Pharmacological
Actions
▪Sedation, Hypnosis, Anxiolysis
▪Anticonvulsant
▪Amnesia
▪Muscle relaxation
▪Euphoria
▪Central muscle relaxation
▪Epileptogenesis
▪↓drug craving
▪Antinociception
▪Cognitive impairment
▪↓hormone release