Newland, Claire Fiona; (1990) Properties of the gamma-aminobutyric acid activated chloride channels in mammalian neurones. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

GABAA receptor-channels in dissociated rat sympathetic ganglion neurones have been studied by conventional patch clamp techniques, with both whole-cell and outside-out patch configurations. These GABAA receptor-channels are shown to be pharmacologically similar to those of mammalian central neurones, being inhibited by bicuculline, picrotoxin, picrotoxinin and penicillin, and potentiated by pentobarbitone. Furthermore, peripheral GABAA-channels resemble central ones in their current-voltage relationship (whole-cell and single-channel) and in the voltage-dependence of their kinetic properties (noise analysis). The mechanism of action of the well established GABAA antagonist, picrotoxin, has been further investigated in these neurones. The effects of picrotoxin on GABA noise, on the GABA current-voltage relationship, and on single-channel currents have been considered. Also the rate of onset of block by picrotoxin was found to be ‘use-dependent’. Based on these results and previous reports, the mechanism of action of picrotoxin appears to be a complex channel block rather than an open channel block, as originally proposed. The analysis of GABAA single-channel currents evoked by high concentrations of GABA has provided basic information about the kinetic behaviour of this receptor-channel in rat superior cervical ganglion neurones. Analysis of the 'probability of being open' of these channels has revealed kinetic heterogeneity, which was not apparent from previously reported single-channel analysis employing low agonist concentrations. Randomization testing of observed and simulated single-channel activity (simulated activity of identical and independent channels) verify that this kinetic heterogeneity was a real phenomenon. The most frequently observed conductance level of the GABAA receptor-channels in these neurones (measured from single-channel currents) was approximately 30pS (at room temperature). Conductance levels of 15-18pS and 22-23pS were also common, while conductance levels of 33-36pS and 7-9pS were occasionally, but reliably observed. Increasing the temperature or reducing the pH, increased the amplitude of the most frequently occurring conductance level.

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