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

Eduard Stefan (), Mohan K. Malleshaiah, Billy Breton, Po Hien Ear, Verena Bachmann, Michael Beyermann, Michel Bouvier and Stephen W. Michnick ()
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Eduard Stefan: Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck
Mohan K. Malleshaiah: Université de Montréal
Billy Breton: Université de Montréal
Po Hien Ear: Université de Montréal
Verena Bachmann: Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck
Michael Beyermann: Leibniz-Institut für Molekulare Pharmakologie
Michel Bouvier: Université de Montréal
Stephen W. Michnick: Université de Montréal

Nature Communications, 2011, vol. 2, issue 1, 1-10

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1605

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