Sites of positive allosteric modulation by neurosteroids on ionotropic gamma-aminobutyric acid receptor subunits.
Neurosteroids are known as allosteric modulators of ionotropic gamma-aminobutyric acid (GABA) receptors. Here, we investigated sites of positive allosteric modulation by allotetrahydrodeoxycorticosterone (5alpha-THDOC) at GABA receptors using the technique of chimeragenesis and the Xenopus oocyte expression system. Our findings have demonstrated that the region from transmembrane segment (TM) 4 to the C-terminus of the GABA(A) receptor alpha1 subunit is crucial for the action of 5alpha-THDOC, but insufficient for the action of another neurosteroid allopregnanolone, suggesting that a specific region critical for neurosteroid action at GABA receptors exists in the domain between TM4 and the C-terminus of GABA receptor subunits.
Ueno
Susumu
S
Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu, Fukuoka 807-8555, Japan. susumu@med.uoeh-u.ac.jp
Tsutsui
Masato
M
Toyohira
Yumiko
Y
Minami
Kouichiro
K
Yanagihara
Nobuyuki
N
D000494:Allosteric Regulation; D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D058785:GABA-A Receptor Agonists; D006801:Humans; D008969:Molecular Sequence Data; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011280:Pregnanolone / Q000494:pharmacology*; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics; D011994:Recombinant Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics; D029867:Xenopus Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics; D014982:Xenopus laevis
D058785:GABA-A Receptor Agonists; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D029867:Xenopus Proteins; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D011280:Pregnanolone