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, and it signals through heterotrimeric G proteins to activate a variety of effectors including G protein-coupled inwardly-rectifying potassium channels (GIRKs)1,2. GABAB receptor signaling is tightly regulated by auxiliary subunits called KCTDs, which control the kinetics of GIRK activation and desensitization3–5. However, the mechanistic basis for KCTD modulation of GABAB signaling remains incompletely understood. Here, using a combination of X-ray crystallography, electron microscopy, functional and biochemical experiments we reveal the molecular details of KCTD binding 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 further 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. These results provide a framework for understanding the molecular basis for the precise temporal control of GABAB signaling by KCTD proteins.