PKA is a tetrameric holoenzyme consisting of 2 regulatory subunits (R) and 2 catalytic subunits (C). Binding of cAMP to the regulatory subunits activates PKA by displacing the catalytic subunits, allowing target protein phosphorylation. PKAs are localized to specific intracellular regions by A kinase anchor proteins (AKAPs). G protein-coupled receptors (GPCRs) can stimulate or inhibit cAMP production via Gs (stimulatory) and Gi (inhibitory) α subunits of heterotrimeric G proteins coupled to adenylyl cyclases. Phosphodiesterases degrade cAMP to AMP. A homozygous missense mutation in the PRKACG gene (p.74Ile>Met) encoding the γ-catalytic subunit of PKA causes inherited macrothrombocytopenia. The inability of the defective PKA to phosphorylate target proteins results in decreased filamin A (FLNa) in MK and platelets, decreased MK proplatelet formation, increased platelet cAMP, and abnormal platelet function. Illustration by Yuriy Baglaenko, University of Toronto.