α1β2γ2 GABAA receptors mediate most inhibitory synaptic transmission in the brain, and are the target of widely used therapeutic drugs such as benzodiazepines. Upon activation by the neurotransmitter, they undergo activation and desensitization transitions. Researchers from the Channel Receptors Unit showed that they undergo asymmetric motions during desensitization, with potential implications in pharmacology.
Ligand-gated ion channels mediate chemical synaptic transmission and are key players of neuronal communication and neuronal network computation. Upon neurotransmitter binding, these allosteric proteins undergo fast conformational transitions to open their intrinsic channel on the millisecond timescale, generating the electric signal. Soon after their discovery in the 60s, it was also recognized that they undergo a slower transition, called desensitization, which corresponds to the closing of the channel in the prolonged presence of the neurotransmitter. The molecular mechanism of this process remained ill-defined. In the present work, Researchers from the Channel Receptors Unit focused on α1β2γ2 GABAA receptors that mediate most inhibitory synaptic transmission in the brain of vertebrates and are the target of benzodiazepines. These receptors are pentameric complexes with pseudo five-fold symmetry, composed of two α1, two β2 and one γ2 subunit. To explore the mechanism of desensitization, the team used concatemeric α1β2γ2 GABAA receptors where the five subunits are fused in a single gene, in order to selectively introduce gain-of-desensitization mutations one subunit at a time. Introducing mutations at the different subunits shows a strongly asymmetric pattern with a key contribution of the γ2 subunit, and combining mutations results in marked synergistic effects indicating a non-concerted mechanism. Kinetic modelling indeed suggests a pathway where subunits move independently, the desensitization of two subunits being required to occlude the pore. In conclusion, while the active and desensitized states of GABAA receptors likely display symmetric architectures, as implemented in the landmark Monod-Wyman-Changeux theory developed 50 years ago in the Institut Pasteur, the conformational pathway of desensitization involves transient asymmetric motions. This hints towards a very diverse and labile conformational landscape during desensitization, with potential implications in physiology and pharmacology.