title: PKA regulatory subunits mediate synergy among conserved G-protein-coupled receptor cascades.
abstract: 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.
authors.affiliation: Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria. eduard.stefan@uibk.ac.at
authors.forename: Eduard
authors.initials: E
authors.lastname: Stefan
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Malleshaiah
authors.forename: Billy
authors.initials: B
authors.lastname: Breton
authors.forename: Po Hien
authors.initials: PH
authors.lastname: Ear
authors.forename: Verena
authors.initials: V
authors.lastname: Bachmann
authors.forename: Michael
authors.initials: M
authors.lastname: Beyermann
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Michnick
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014169:Transformation, Bacterial
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D021122:Protein Subunits; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D019950:Mitogen-Activated Protein Kinase 1