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 G a-proteins route signals to interconnected effector cascades, thus regulating thresholds, amplitudes and durations of signalling. G a s-or G a i-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 G alpha s-coupled receptor cascades, the regulatory subunit type-II (RII) of protein kinase A undergoes adenosine 3'-5'-cyclic monophosphate ( cAMP)dependent binding to G alpha i. Stimulation of a mammalian G alpha i-coupled receptor and concomitant cAMP-RII binding to G alpha i, augments the sensitivity, amplitude and duration of G alpha i: beta gamma. 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 fi ndings suggest a direct mechanism by which coincident activation of G alpha s-coupled receptors controls the precision of adaptive responses of activated G alpha i-coupled receptor cascades.