The g -aminobutyric acid type A (GABAA) receptor b3 homomer is highly sensitive to noncompetitive antagonist binding. b1 homomer retains only about 10% binding activity of b3 homomer. This study test the potency difference of b1 and b3 homomer using mutagenesis, chimeragenesis, heteromer combined with a1 subunit and agonist GABA as modulator. Chimer 1(CH1) containing extracellular half of the b3 and b1 transmembrane domains retained about 70% binding level of b3 homomer. Chimer 2 (CH2) with extracellular half of the b1 and b3 transmembrane domains had similar binding activity to b1 homomer. GABA stimulated heteromer a1b1 and a1b3 binding level to 2.0-2.5 folds at 3 mM. Addition of a1 subunit rescued the inactive CH2 close to wildtype a1b1 and 3 mM GABA also increased a1CH2 to high binding activity. Therefore, NCA binding site is tightly regulated by the open-state conformation occupied by receptor that largely decides the sensitivity of GABAA receptor.

Effect of GABA<sub>A</sub> receptor subunit composition and agonist on noncompetitive antagonist sensitivity and selectivity

239th National Meeting (2010)

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Effect of GABAA receptor subunit composition and agonist on noncompetitive antagonist sensitivity and selectivity

Effect of GABA_A receptor subunit composition and agonist on noncompetitive antagonist sensitivity and selectivity