GABA- GABAA

Question 1

Neuropharmacology of the GABAA receptor

Answer 1

Question 2

Which drugs modulate the GABAA receptor

Answer 2

Ethanol, benzodiazepines, barbiturates, competitive antagonists, non-competitive antagonists, neurosteroids

Question 3

Which drugs act at the agonist binding site in GABAA?

Answer 3

Muscimol/agarin (major psychoactive alkaloid in mushrooms) Bicuculline (Toxin from Dicentra cucullaria (Dutchman’s breeches) (Used by native N. Americans for syphilis) NB: these are mostly used in a research setting

Question 4

Benzodiazepines

Answer 4

Benzodiazepine agonist increase channel opening frequency bind at the alpha-gamma interface 75% of GABA receptors are benzodiazepine sensitive

Question 5

Barbiturates

Answer 5

Bind 50 angstroms below the GABA binding site in a water accessible pocket formed between the four transmembrane helices High physical and psychological addiction potential barbiturates stabilise open state so increase channel open time much more toxic than benzodiazepines

Question 6

Properties of the NCA site

Answer 6

TM2 residues all 5 subunits Accommodates diverse chemical structures Causes blockade of the 8.5-Å channel pore

Question 7

ligands at the NCA site

Answer 7

Picrotoxin (PTX): From Cocculus indicus,(fruit of Anamirta paniculata);Potent poison: delirium, convulsions, paralysis, death α-Thujone: From wormwood – illegal absinthe (Green Fairy)

NB ligands at NCA site are specific to chloride channels not GABA

Question 8

Neurosteroids e.g. pregnenolone

Answer 8

Synthesized in CNS and PNS (myelinating glia from periphery) Accumulate in brain: local synthesis or metabolism, esp. testosterone +ve allosteric modulators of the GABAA receptor, enhancing GABA function 2 modes: Direct activation – α/β interface; Potentiation GABA responses via cavity formed by TM domains

Question 9

Ethanol

Answer 9

Positive modulator

Question 10

Propofol

Answer 10

Short acting hypnotic, induction/maintenance general anaesthesia +ve allosteric modulator of the GABAA receptor, enhancing GABA function Multiple binding sites – may prefer extra-synaptic, high affinity GABAA receptors V. narrow therapeutic window – easy to OD

Question 11

Intra-receptor drug interactions

Answer 11

Increased potentiation of GABA’s inhibitory effects –> Additive CNS and respiratory depressant effects e.g: Alcohol and barbiturates; Propofol and benzodiazepines; Barbiturates also ↑ binding affinity of BDZ sites - ↑ effect of benzodiazepines. Increased potentiation of GABA receptor antagonism–> Additive CNS excitatory effects - convulsions Confounding effects: ↑ GABAR agonism combined with ↑ antagonism: Picrotoxin (NCA site) antidote in poisoning by CNS depressants (barbiturates)

Question 12

GABAA receptor diversity and pharmacology

Answer 12

See other card

Question 13

Most common GABAA receptor in the brain

Answer 13

2α1:2βn:γ2 where n= 1-3

Question 14

What do the permutations of GABAA receptors affect?

Answer 14

Functional properties and trucking properties (draw diagrams)

Question 15

Subunit alpha-1

Answer 15

Sedative effects of benzodiazepine agonists

Question 16

Subunits alpha-2 and alpha-3

Answer 16

Anxiolytic effects of benzodiazepine agonists (high in cortex and amygdala) Alpha-3 also involved in muscle relaxant

Question 17

Subunit Delta

Answer 17

Mediates neurosteroid effects

Question 18

GABAB receptors

Answer 18

G-protein coupled (Gαi / Gαo) Dimer Pre (and postsynaptic) localisations

Question 19

GABAB receptor agonists

Answer 19

Baclofen: only potent agonist in clinical use (muscle relaxant) useful for treating spastic movement disorders (action is spinal / supraspinal) alcoholism

Question 20

GABAB competitive antagonists

Answer 20

Saclofen Phaclofen

Question 21

Mechanism of action of GABAB receptors

Answer 21

increase K+ channels decrease Ca2+ channels decrease adenylate cyclase TR EK-2, a type of two-pore domain K+ (K2P) channels Reduced activity of presynaptic VGCa channels Reduce open time of NMDA receptors

Question 22

GABAC (Aρ)

Answer 22

Relatively poorly understood First evidence – 1975 –GABA effect in cat spinal neurons that was not blocked by bicuculline (GABAA antagonist) 3 receptor subtypes ρ1-3 (Human) Common ancestor to GABAA Widespread but esp. retina, hippocampus, spinal cord, sup colliculus, pituitary and gut

Question 23

GABAC (Aρ) pharmacology

Answer 23

Agonists: CACA (cis-4-aminocrotonic acid); (+)-CAMP; 5-Methyl-1H-imidazole-4-acetic acid (5-Me-IAA) Competitive Antagonists: TPMPA (1,2,5,6-tetrahydropyridin-4-yl methylphosphinic acid); P4MPA; SGS742; ACPBPA Picrotoxin blocks (as GABAA) Ethanol also blocks (negative modulator – unlike GABAA)