Structural basis for KCTD-mediated rapid desensitization of GABAB signalling

Nature. 2019 Mar;567(7746):127-131. doi: 10.1038/s41586-019-0990-0. Epub 2019 Feb 27.


The GABAB (γ-aminobutyric acid type B) 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 signalling 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 signalling remains incompletely understood. Here, using a combination of X-ray crystallography, electron microscopy, and functional and biochemical experiments, we reveal the molecular details of KCTD binding to both GABAB receptors and G-protein βγ subunits. KCTDs associate with the receptor by forming an asymmetric pentameric ring around a region of the receptor carboxy-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 interact directly with one another. We further show that KCTD binding to Gβγ is highly cooperative, defining a model in which KCTD proteins 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 signalling by KCTD proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Crystallography, X-Ray
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / chemistry
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • GTP-Binding Protein beta Subunits / chemistry
  • GTP-Binding Protein beta Subunits / metabolism
  • GTP-Binding Protein beta Subunits / ultrastructure
  • GTP-Binding Protein gamma Subunits / chemistry
  • GTP-Binding Protein gamma Subunits / metabolism
  • GTP-Binding Protein gamma Subunits / ultrastructure
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Microscopy, Electron
  • Models, Biological
  • Models, Molecular
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / ultrastructure
  • Protein Binding
  • Protein Domains
  • Proteins / chemistry*
  • Proteins / metabolism
  • Proteins / ultrastructure
  • Receptors, GABA-B / chemistry*
  • Receptors, GABA-B / metabolism*
  • Receptors, GABA-B / ultrastructure
  • Signal Transduction*


  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • G-protein Beta gamma
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Intracellular Signaling Peptides and Proteins
  • KCTD12 protein, human
  • KCTD16 protein, human
  • KCTD8 protein, human
  • Nerve Tissue Proteins
  • Proteins
  • Receptors, GABA-B