Mechanism of activation and modulation in human GABA(B) receptor

总结

Summary The inhibitory neurotransmitter GABA produces slow and prolonged inhibition in the brain through activation of metabotropic GABAB receptors. Defects in GABAB signaling have been implicated in various neurological and mood disorders including spasticity, epilepsy, addiction and anxiety. GABAB receptor is a member of the class C G protein-coupled receptor (GPCR) family, which typically functions as a dimer and possesses large extracellular domains. Fundamental questions remain concerning the molecular mechanisms underlying activation and modulation of these class C receptors. The GABAB receptor is a heterodimer of GABAB1 and GABAB2 subunits and is modulated by the potassium channel tetramerization domain-containing (KCTD) protein auxiliary subunits. We are developing structural models for full-length GABAB receptor, its auxiliary subunits and their complexes with G-protein. Based on our structural analysis, we will determine the molecular association between GABAB receptor and KCTD, describe the conformations of full-length GABAB receptor in multiple functional states, and characterize the allosteric interaction between the GABAB receptor and G proteins. Together, these studies will advance our understanding of the molecular basis of GABA action in the brain, leading to the development of novel therapeutics for treating neurological diseases.