Structure and Pharmacology of Vertebrate GABAA Receptor Subtypes

https://doi.org/10.1016/S0074-7742(08)60525-5Get rights and content

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This chapter reviews GABAA receptors and describes how the techniques of molecular neurobiology enabled a revolution in the understanding of the GABAA receptor. In common with the other members of the ligand-gated ion channel family, the function of the GABAA receptor is modulated by phosphorylation. Indeed, purified native GBAA receptor protein can be phosphorylated in vitro by cyclic AMP-dependent protein kinase A (PKA) and calcium/phospholipiddependent protein kinase C (PKC). Analysis of the deduced amino acid sequences of GABAA receptor subunits indicates that the large cytoplasmic loop domains contain consensus sites for phosphorylation by PKA (human α3,α 4, α6, β1, β2, β3,γl , γ2, and γ3), PKC (all human subunits), and tyrosine kinase (γl, γ2, γ3) . It is this domain of the nAChR that undergoes phosphorylation. The pentameric structure of the GABAA receptor is based on analogy with the nicotinic receptor, the physicochemical properties of the solubilized receptor, and electron microscopic studies of purified receptor preparations. A diverse range of both naturally occurring and synthetic compounds can allosterically regulate GABAA receptors. By using recombinant receptors, it is possible to study the roles played by individual subunits in the actions of many of these compounds and indeed, in some cases, individual amino acids located at the binding sites have been identified.

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