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Pharmacological properties of recombinant human GABAA receptors

Thompson, Sally-Anne; (2002) Pharmacological properties of recombinant human GABAA receptors. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

GABA is the major inhibitory neurotransmitter in the vertebrate brain mediating its fast inhibitory action via GABAA receptors. This receptor is a hetero-oligomeric protein with the majority of receptors being composed of several distinct polypeptides (α,β,γ,δ,ε,θ,π,ρ). GABAA receptors are allosterically regulated by a large number of compounds, some of which are in clinical use as anxiolytic, sedative and antiepileptic agents. The aim of this study was to characterise the pharmacological properties of novel GABAA receptor subunits or mutated subunits and to examine, in detail, the pharmacology of specific allosteric modulators. Receptors containing the ϵ subunit and the mutated β2 subunit (β2L259S) exhibit a degree of constitutive-activity while still being sensitive to activation by GABA. α1β1ϵ receptors were not modulated by benzodiazepines, displayed intermediate sensitivity to Zn²⁺ (cf α1β1 and α1β1γ2s), were potentiated by the general anaesthetic agents, pentobarbitone (PB), propofol and etomidate and exhibited rapid desensitization kinetics. In contrast, α1β2L259Sγ2s receptors exhibited slow desensitization kinetics, increased sensitivity to GABA and GABA site agonists and were not modulated by various allosteric modulators. Studying the subtype selectivity of PB revealed distinct differences in the direct activation with α6β2γ2s receptors being significantly more sensitive and having greater efficacy than α1-5β2γ2s receptors. The EC₅₀ for the total modulatory effect of PB however was not influenced by the receptor subtype, unlike the efficacy which depended on the type of α subunit present within the αβγ receptor complex. Mutagenesis studies with the selective antagonist furosemide revealed that the β2/3 selectivity was due to Asn 265 within transmembrane domain (TM) 2, while a significant portion of the α6 selectivity was due to Ile 228 within TM1. The allosteric modulator tracazolate displayed opposing functional effects, with α1β1/3ϵ receptors being inhibited while α1β1/3γ2s receptors were potentiated. This study has therefore provided new information on the pharmacology of a number of allosteric modulators and receptor subtypes.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Pharmacological properties of recombinant human GABAA receptors
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; GABAA receptors
URI: https://discovery.ucl.ac.uk/id/eprint/10103913
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