Benzodiazepine Modulation of GABA(A) Receptors: A Mechanistic Perspective

Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that target GABA(A) receptors (GABA(A)Rs) to tune inhibitory synaptic signaling throughout the central nervous system. Despite knowing their molecular target for over 40 years, we still do not fully understand the mechanism of modulation at the level of the channel protein. Nonetheless, functional studies, together with recent cryo-EM structures of GABA(A)(α1)(2)(βX)(2)(γ2)(1) receptors in complex with BZDs, provide a wealth of information to aid in addressing this gap in knowledge. Here, mechanistic interpretations of functional and structural evidence for the action of BZDs at GABA(A)(α1)(2)(βX)(2)(γ2)(1) receptors are reviewed. The goal is not to describe each of the many studies that are relevant to this discussion nor to dissect in detail all the effects of individual mutations or perturbations but rather to highlight general mechanistic principles in the context of recent structural information.