GABAergic neurotransmission

Question 1

GABA

Answer 1

• main inhibitory NT in CNS
• regulates neuronal excitability
• acts at inhibitory synapses by binding to receptors in PM of both pre and postsynaptic processes
• binding causes opening of ion channel- Cl-in or K+out -> hyper polarization
• GABAa: ligand-gated ion channel complex
• GABAb: metabotropic receptor
• cannot penetrate blood-brain barrier

Question 2

GABA synthesis

Answer 2

Glu - GLUTAMIC ACID DECARBOXYLASE - GABA

• cytosolic enzyme
• 2 isoforms: GAD65 and GAD 67
• inhibition leads to convulsion

Question 3

Degradation of GABA

Answer 3

GABA + alphaKG -> Succinic semialdehyde + Glu -> Succinate

• GABA transaminase enzyme
• mitochondrial enzyme
• requires PLP
• inhibited by gamma-vinyl GABA

Question 4

GAT transporters

Answer 4

• astrocytes
• Na+ dependent
• works agains conc. gradient
• bidirectional
  GAT1: presynaptic terminal
  GAT2: extrasynaptic region
  GAT3: astrocytic processes
  Inhibitors: anticonvulsants

Question 5

GABA a receptor

Answer 5

• ionotropic receptor, ligand-gated ion channel
• conducts Cl- through pore - hyperpolarization
• active site is binding site for GABA, muscimol, gaboxadol, bicuculline
• many different allosteric binding sites

Question 6

Structure of GABA a receptor

Answer 6

• pseudo-symmetrical pentamer
• chloride ion channel
• 1 homolog subunit - 4 domains
• 1 membrane spanning domain - forms chloride channel
• 3 others surround it
• disulfide bonds in N terminal extracellular domain- cys-loop receptors
• subunits form at least 19 polypeptides
• phosphorylation sites on each subunit

Question 7

Barbiturates

Answer 7

• CNS depressants- mild sedation to total anesthesia
• also anxiolytics, hypnotics and anticonvulsants + analgesic effect
• addiction potential
• positiv allosteric modulation of GABA a receptor
• bind to beta subunit
• also block AMPA receptor

Question 8

Benzodiazepines

Answer 8

• psychoactive drugs
• most common: Diazepam (Valium)
• enhance effect of GABA at GABA a receptor
• sedative, hypnotic, anxiolytic, anticonvulsant and muscle relaxant effect
• promotes GABA binding
• Chlordiazepoxide: used for alcohol detoxification
• Oxazepam and Lorazepam for patient with risk of drug accumulation