Eur J Pharmacol 2003 Aug 22;4761-2:17-24. doi: 10.1016/s0014-2999(03)02125-3.

Pharmacology of GABA(A) receptors exhibiting different levels of spontaneous activity.

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The present study examines the spontaneous channel activity of GABA(A) receptors and the pharmacology of various full agonists (gamma-aminobutyric acid (GABA), isoguvacine), partial agonists (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP), piperidine-4-sulphonic acid (P4S), imidazole-4-acetic acid), competitive antagonists (bicuculline, 2-(3-carboxypropyl)-3-amino-6-(4 methoxyphenyl)pyridazinium bromide (SR95531)) and non-competitive antagonists (picrotoxinin, zinc). Experiments were performed on oocytes separately expressing human alpha1beta2gamma2S, alpha1beta3epsilon and alpha1beta2(L259S)gamma2S receptors using two-electrode voltage clamp electrophysiology. Quantifying spontaneous channel activity showed this varied significantly between the alpha1beta2gamma2S (0.2+/-0.07%), alpha1beta3epsilon (20+/-3%) and alpha1beta2(L259S)gamma2S (83+/-4%) receptors. A direct correlation was found between the relative agonist potencies and the level of spontaneous activity of the GABA(A) receptors. Furthermore, the maximum responses for partial agonists were increased as a function of increased levels of spontaneous activity. There was no relationship between the potency/efficacy of competitive antagonists and the degree of spontaneous activity. However, the non-competitive allosteric inhibitor picrotoxinin showed an opposite dependence on spontaneous activity compared to that seen for agonists, whereas zinc showed a more complex dependence on the receptor subunit composition. These novel findings indicate that the potency and efficacy of ligands acting on GABA(A) receptors are highly dependent on the level of spontaneous activity of the receptor.

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