Differential roles for the M2-M3 linkers of specific GABAAR subunits in pore stability and benzodiazepine modulation

Abstract

GABAA receptors are neurotransmitter-gated ion channel critical for inhibitory synaptic transmission as well as the molecular target for many psychotropic drugs. Of these, benzodiazepines (BZDs) are some of the most widely prescribed. However, the physical basis of their modulation is poorly understood. We previously exploited a gain of function mutant (α1L9'Tβ2γ2L) that can be directly activated by BZDs alone in the absence of GABA to identify a critical residue in the α1 M2—M3 linker (V279) mediating coupling between the BZD site and the pore gate (PMC7899671).