Structure and Function of GABA-A receptors

Abstract GABAA receptors are the major inhibitory neurotransmitter receptors in the brain and targets of important therapeutics and drugs of abuse. Given their susceptibility to diverse therapeutic and abused compounds and their involvement in anxiety disorders, excitotoxicity, and epilepsy, a comprehensive understanding of this receptor is imperative. In this competing renewal application, we build upon our initial elucidation of structures of the α1β2γ2 GABAA receptor subtype. Specific projects span structural pharmacology, the mechanisms underlying ion channel gating, and studies of receptors in healthy and diseased brain tissue. Our proposed efforts in structural pharmacology focus on unexplored drug classes including allosteric modulators used in the clinic and prominently abused drugs. We propose to first identify binding sites, then interrogate mechanisms of potentiation through a combination of functional assays and computational approaches. Concurrently, we propose to address a significant gap in our understanding of GABAA receptor signaling, the structure-based mechanism for channel gating. Employing time-resolved cryo- EM techniques coupled with molecular dynamics, our aim is to capture the activated state, mapping transitions among resting, activated, and desensitized states. To better understand the assemblies of GABAA receptors found in their native environments, we propose to develop approaches for mapping subunit arrangements in receptors in brain tissue. We propose to examine distinct brain regions to provide insights relevant to targeted therapeutic interventions. This comprehensive, multidisciplinary approach integrates structural biology, electrophysiology, and computational analyses, yielding an expanded understanding of GABAA receptors relevant to basic signaling mechanisms, drug abuse, and drug development.