Intersubunit communication in the GABA(A) receptor

The GABAA receptor is the major inhibitory ligand-gated ion channel in the mammalian central nervous system, and its activity contributes to the regulation of neuronal firing rates and network oscillations important for normal cognitive behavior. It can be modulated by a host of clinically relevant compounds including anesthetics and benzodiazepines, and several genetic mutations in the genes encoding it cause human pathologies such as epilepsy. The channel is composed of five subunits around a central pore, with the interfaces between subunits having important functional roles. For example, GABA binds at one set of interfaces to trigger channel activation, benzodiazepines bind at another interface to modulate channel activity, and a point mutation at yet another interface causes epilepsy in humans. Here, we explore how perturbations at an individual intersubunit interface are propagated to the ligand binding domains of the other interfaces by determining their effect on the microscopic kinetics of ligand binding and unbinding. We propose a simple physical mechanism that can account for our observations, as well as a number of other aspects of GABAA receptor behavior. This mechanism predicts the effects of an expansion or contraction of one interface on ligand binding kinetics at all of the interfaces. If correct, our hypothesis may prove to be a powerful tool not only in aiding understanding of the behavior of multisubunit proteins such as ligand-gated ion channels, but also in the rational design of novel drugs that modulate them.