Activation of the two ubiquitous families of protein kinases, protein kinase A (PKA) and protein kinase C (PKC), is thought to be independently coupled to stimulation of G␣ s and G␣ q , respectively. Live-cell confocal imaging of protein kinase C fluorescent protein fusion constructs revealed that simultaneous activation of G␣ s and G␣ q resulted in a differential translocation of the conventional PKC␣ to the plasma membrane while the novel PKC␦ was recruited to the membrane of the endoplasmic reticulum (ER). We demonstrate that the PKC␦ translocation was driven by a novel G␣ s -cyclic AMP-EPAC-RAP-PLC pathway resulting in specific diacylglycerol production at the membrane of the ER. Membrane-specific phosphorylation sensors revealed that directed translocation resulted in phosphorylation activity confined to the target membrane. Specific stimulation of PKC␦ caused phosphorylation of the inositol-1,4,5-trisphosphate receptor and dampening of global Ca 2؉ signaling revealed by graded flash photolysis of caged inositol-1,4,5-trisphosphate. Our data demonstrate a novel signaling pathway enabling differential decoding of incoming stimuli into PKC isoform-specific membrane targeting, significantly enhancing the versatility of cyclic AMP signaling, thus demonstrating the possible interconnection between the PKA and PKC pathways traditionally treated independently. We thus provide novel and elementary understanding and insights into intracellular signaling events.