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Title: Pharmacology of GABA receptors in Ascaris suum muscle : an electrophysiological study
Author: Duittoz, Anne Helene
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1991
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The aim of this work is to describe the pharmacological profile of the Ascaris muscle GABA receptor, and to compare its properties to those of GABA receptors in vertebrates. The interest of such study is to show the existence of pharmacological differences between Ascaris and vertebrate GABA receptors, which may be exploited in antiparasitic drug research. The effects of GABA and various GABA-agonists on the membrane input conductance of Ascaris muscle cells were studied using a current-clamp technique. Dose-response curves were obtained and described by a modified Hill equation for each agonist tested. The relative potencies of GABA-agonists inAscaris are compared to those obtained at vertebrate GABA-A receptors. Despite some differences: inactivity of sulphonic acid derivatives and the loss of relative potency of rigid analogues of GABA, such as muscimol, THIP and isoguvacine, the agonist profile of Ascaris muscle GABA receptor appears correlated with the agonist profile of vertebrate GABA-A receptor. In contrast, the antagonist profile of Ascaris GABA receptors differs greatly from the antagonist profile of the vertebrate GABA-A receptor. The two classical GABA-A antagonists, picrotoxin and bicuculline, were found very weak or inactive at antagonizing GABA responss in Ascaris. The steroid derivative, RU135, a potent competitive antagonist in vertebrate, was found to hold back some activity in Ascaris, but in a non competitive manner and with a low potency. The arylaminopyridazine GABA derivative, SR95103, appeared more potent than its close analogue SR95531 at antagonizing GABA responses in Ascaris; this potency order contrasts with what is found at vertebrate GABA-A receptors. A modified Schild analysis was used to describe the action of SR95103, the data is consistent with a competitive mechanism involving two molecules of GABA but one molecule of antagonist interacting with the receptor. The estimated KB for SR95103 is 64±13μM (mean±SE, n = 14) and the pA_2 = 4. The actions of SR95103 were further examined on GABA-activated single-channel currents using an outside-out patch-clamp technique. The presence of SR95103 (30-1-μM) did not alter the GABA-activated channel main conductance, but reduced the open-probability of the channels. The mode of action of SR95103 is discussed, and it is suggested that most of the antagonism is competitive and produced by a single molecule of SR95103 combining with the receptor-channel complex. An additional non-competitive component, possibly a channel block, is detected only at high concentration. The lack of activity of classical GABA-A antagonists and the difference in potency order for SR95103 and SR95531 found in Ascaris, is explained by the existence of different accessory binding sites responsible for the binding of antagonists.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available