The present invention relates to novel methods of signal transduction in cells. In particular, the invention relates to signal transduction via a class of enzymes known as phosphodiesterase enzymes or PDEs. The invention also relates to a class of signaling molecules known as G-coupled protein receptors (GCPRs) and G-proteins. The invention provides novel methods to screen for and identify G-proteins and other compounds which modulate signaling by these two classes of proteins. In particular, the relates to novel assays which identify compounds that modulate (e.g., enhance or inhibit) binding between a PDE polypeptide and an effector activation domain of a G-protein.