The neurotransmitter gamma-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABAARs). These receptors are assembled as pentamers surrounding a central ion-conducting pore that open in response to ligand binding in the extracellular domain, and they can be either homo- or heteropentameric. With 19 different GABAAR genes, they provide a remarkable diversity in neuronal response and regulation.
The pharmacological properties of the rho-type GABAARs are particularly distinctive - to the extend that these receptors were originally believed to constitute a separate "type C" GABA receptor class. I will present our work on the cryo-EM structure determination of the rho-type receptors, and how we have both been able to capture receptors in a whole range of functional states and explain their unique pharmacology. Comparative structures, mutant recordings, and molecular simulations with and without GABA explain the sensitized but slower activation of rho receptors relative to the canonical neuronal subtypes, and we have also been able to identify new unique allosteric modulation binding sites. Finally, I will share very recent work a5b3 heteromeric receptors, and show how cryo-EM and advanced processing makes it possible to resolve subpopulations of different assemblies in a single sample.