Structural basis for KCTD-mediated rapid desensitization of GABAB signalling

Abstract

The GABAB receptor is one of the principal inhibitory neurotransmitter receptors in the brain, signaling through heterotrimeric G proteins to activate a variety of effectors including G protein-coupled inwardly-rectifying potassium channels (GIRKs). GABAB receptor signaling is tightly regulated by auxiliary subunits called KCTDs, which control the kinetics of GIRK activation and desensitization. Using a combination of X-ray crystallography, electron microscopy, functional and biochemical experiments we show how KCTDs bind to both GABAB receptors and Gβγ subunits. KCTDs associate with the receptor by forming an asymmetric pentameric ring around a region of the receptor C-terminal tail, while a second KCTD domain, H1, engages in a symmetric interaction with five copies of Gβγ in which the G protein subunits also directly interact with one another. We show that KCTD binding to Gβγ is highly cooperative, defining a model in which KCTDs cooperatively strip G proteins from GIRK channels to induce rapid desensitization following receptor activation.