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PKA regulatory subunits mediate synergy among conserved G-protein-coupled receptor cascades.

G-protein-coupled receptors sense extracellular chemical or physical stimuli and transmit these signals to distinct trimeric G-proteins. Activated Gα-proteins route signals to interconnected effector cascades, thus regulating thresholds, amplitudes and durations of signalling. Gαs- or Gαi-coupled receptor cascades are mechanistically conserved and mediate many sensory processes, including synaptic transmission, cell proliferation and chemotaxis. Here we show that a central, conserved component of Gαs-coupled receptor cascades, the regulatory subunit type-II (RII) of protein kinase A undergoes adenosine 3'-5'-cyclic monophosphate (cAMP)-dependent binding to Gαi. Stimulation of a mammalian Gαi-coupled receptor and concomitant cAMP-RII binding to Gαi, augments the sensitivity, amplitude and duration of Gαi:βγ activity and downstream mitogen-activated protein kinase signalling, independent of protein kinase A kinase activity. The mechanism is conserved in budding yeast, causing nutrient-dependent modulation of a pheromone response. These findings suggest a direct mechanism by which coincident activation of Gαs-coupled receptors controls the precision of adaptive responses of activated Gαi-coupled receptor cascades.

Pubmed ID: 22186894


  • Stefan E
  • Malleshaiah MK
  • Breton B
  • Ear PH
  • Bachmann V
  • Beyermann M
  • Bouvier M
  • Michnick SW


Nature communications

Publication Data

December 21, 2011

Associated Grants

  • Agency: Canadian Institutes of Health Research, Id: MOP-FRN-10501
  • Agency: Canadian Institutes of Health Research, Id: MOP-GMX-152556
  • Agency: NIGMS NIH HHS, Id: U54 GM062114

Mesh Terms

  • Adaptation, Physiological
  • Cloning, Molecular
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinase Type II
  • Escherichia coli
  • GTP-Binding Protein alpha Subunits
  • Gene Expression Regulation, Fungal
  • Mitogen-Activated Protein Kinase 1
  • Mutation
  • Phosphorylation
  • Plasmids
  • Protein Binding
  • Protein Subunits
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Signal Transduction
  • Transformation, Bacterial