The beta subunit determines the ion selectivity of the GABAA receptor.
The gamma-aminobutyric acid, type A (GABA(A)) receptor is a chloride-conducting receptor composed of alpha, beta, and gamma subunits assembled in a pentameric structure forming a central pore. Each subunit has a large extracellular agonist binding domain and four transmembrane domains (M1-M4), with the second transmembrane (M2) domain lining the pore. Mutation of five amino acids in the M1-M2 loop of the beta(3) subunit to the corresponding amino acids of the alpha(7) nicotinic acetylcholine subunit rendered the GABA(A) receptor cation-selective upon co-expression with wild type alpha(2) and gamma(2) subunits. Similar mutations in the alpha(2) or gamma(2) subunits did not lead to such a change in ion selectivity. This suggests a unique role for the beta(3) subunit in determining the ion selectivity of the GABA(A) receptor. The pharmacology of the mutated GABA(A) receptor is similar to that of the wild type receptor, with respect to muscimol binding, Zn(2+) and bicuculline sensitivity, flumazenil binding, and potentiation of GABA-evoked currents by diazepam. There was, however, an increase in GABA sensitivity (EC(50) = 1.3 microm) compared with the wild type receptor (EC(50) = 6.4 microm) and a loss of desensitization to GABA of the mutant receptor.
Jensen
Marianne L
ML
NeuroSearch A/S, Pederstrupvej 93, Ballerup DK-2750, Denmark.
Timmermann
Daniel B
DB
Johansen
Tina H
TH
Schousboe
Arne
A
Varming
Thomas
T
Ahring
Philip K
PK
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D007473:Ion Channels / Q000502:physiology*; D009118:Muscimol / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000502:physiology; D011978:Receptors, Nicotinic / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D015032:Zinc / Q000494:pharmacology
D007473:Ion Channels; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D011993:Recombinant Fusion Proteins; D009118:Muscimol; D015032:Zinc; D001640:Bicuculline