The main determinant of furosemide inhibition on GABA(A) receptors is located close to the first transmembrane domain.
Inhibitory GABA(A) receptors are regulated by numerous allosteric modulators, the most receptor-subtype specific of which is furosemide. It recognises receptors of the subunit composition alpha6beta2/3gamma2, restricted to cerebellar granule cells. To locate furosemide's site of action we constructed chimeras of the furosemide-sensitive alpha6 and the furosemide-insensitive alpha1 subunit, and expressed and studied them together with the beta3 and gamma2 subunits in Xenopus oocytes by the two-electrode voltage clamp technique. The inhibition of GABA-induced currents by furosemide mainly depended on a short domain proximal to the first transmembrane region of the alpha6 subunit.
Jackel
C
C
Department of Psychiatry, University of Mainz, Germany.
Kleinz
R
R
Mäkelä
R
R
Hevers
W
W
Jezequel
S
S
Korpi
E R
ER
Lüddens
H
H
D000494:Allosteric Regulation; D000818:Animals; D001483:Base Sequence; D002462:Cell Membrane / Q000502:physiology*; D005665:Furosemide / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D014981:Xenopus
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D005665:Furosemide