Studies on the mechanisms of action of picrotoxin, quercetin and pregnanolone at the GABA rho 1 receptor

Br J Pharmacol. 2004 Feb;141(4):717-27. doi: 10.1038/sj.bjp.0705657. Epub 2004 Jan 19.


1. The mechanisms of action of antagonists of the gamma-aminobutyric acid C (GABA(C)) receptor picrotoxin, quercetin and pregnanolone were studied. 2. Ionic currents (chloride), mediated through human homomeric GABA rho(1) receptors expressed in Xenopus oocytes, were recorded by two-electrode voltage clamp. 3. Dose-response (D-R) curves and kinetic measurements of GABA rho(1) currents were carried out in the presence or absence of antagonists. Use-dependent actions were also evaluated. 4. Picrotoxin, quercetin and pregnanolone exerted noncompetitive actions. 5. IC(50) values measured at the EC(50) for GABA (1 microM) were as follows: picrotoxin 0.6+/-0.1 microM (Hill coefficient n=1.0+/-0.2); quercetin 4.4+/-0.4 microM (n=1.5+/-0.2); pregnanolone 2.1+/-0.5 microM (n=0.8+/-0.1). 6. These antagonists produced changes only in the slope of the linear current-voltage relationships, which was indicative of voltage-independent effects. 7. The effect of picrotoxin on GABA rho(1) currents was use-dependent, strongly relied on agonist concentration and showed a slow onset and offset. The mechanism was compatible with an allosteric inhibition and receptor activation was a prerequisite for antagonism. 8. The effect of quercetin was use-independent, showed relatively fast onset and offset, and resulted in a slowed time course of the GABA-evoked currents. 9. The effect of pregnanolone was use-independent, presented fast onset and a very slow washout, and did not affect current activation. 10. All the antagonists accelerated the time course of deactivation of the GABA rho(1) currents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Complementary / biosynthesis
  • DNA, Complementary / genetics
  • Dose-Response Relationship, Drug
  • Electrophysiology
  • Evoked Potentials / drug effects
  • GABA Antagonists / pharmacology*
  • Humans
  • Kinetics
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • Picrotoxin / pharmacology*
  • Pregnanolone / pharmacology*
  • Quercetin / pharmacology*
  • Receptors, GABA-B / drug effects*
  • Receptors, GABA-B / genetics
  • Recombinant Proteins / drug effects
  • Xenopus laevis
  • gamma-Aminobutyric Acid / pharmacology


  • DNA, Complementary
  • GABA Antagonists
  • GABA type B receptor, subunit 1
  • Receptors, GABA-B
  • Recombinant Proteins
  • Picrotoxin
  • gamma-Aminobutyric Acid
  • Quercetin
  • Pregnanolone