Cyclic GMP/Protein Kinase Localized Signaling and Disease Implications

Cyclic guanosine 3′,5′-monophosphate (cGMP) and its downstream target, protein kinase G (PKG or cGK), play central roles in cellular regulation and are important to cardiovascular homeostasis and disease pathophysiology. Cyclic GMP is synthesized via either nitric oxide (NO) or natriuretic peptide (NP) stimulation pathways, each coupled to corresponding cyclases, and catabolized by select members of the phosphodiesterase superfamily. Growing evidence now supports control of cGMP and PKG in distinct microdomains within the myocyte, which results in differential downstream targeting. This regional control stems from distinct localization of the relevant signaling components and their capacity to translocate in the cell under both physiological and pathophysiological conditions to further impact the net response. This chapter discusses current understanding of microdomain regulation of the cGMP/PKG pathway, as this information is important to optimally leverage their effects for the treatment of cardiovascular disease.