The article discusses the role of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in cellular signaling, focusing on the cGMP-dependent protein kinase I (PKG I) isozymes. NO, a small gaseous molecule, is synthesized by nitric oxide synthases (NOS) and acts as a signaling molecule in various physiological processes, including vascular smooth muscle relaxation and platelet aggregation. The production of cGMP from NO is catalyzed by guanylyl cyclases (GCs), which are activated by NO. cGMP levels are regulated by the balance between GCs and cyclic nucleotide phosphodiesterases (PDEs). The article highlights the importance of PKG I isozymes in mediating the effects of increased cGMP levels. PKG I isozymes (PKG Iα and PKG Iβ) are activated by cGMP binding to allosteric sites and undergo autoinhibition in the absence of cGMP. PKG Iα has a higher affinity for cGMP than PKG Iβ, and both isozymes have distinct substrate specificities and subcellular localizations. PKG I isozymes can be localized to specific compartments within cells and can translocate between compartments in response to changes in cGMP levels. The article also discusses the cross-talk between cGMP-dependent protein kinases and cGMP-gated cation channels, as well as the regulation of PKG I by cGMP-hydrolyzing PDEs. The effects of NO-induced increases in cGMP on various cellular processes, such as calcium homeostasis, gene expression, and vasodilation, are reviewed. Additionally, the article explores the therapeutic potential of targeting the NO/cGMP/PKG signaling pathway, including the development of drugs that inhibit PDEs to enhance NO/cGMP signaling. Overall, the article provides a comprehensive overview of the mechanisms and biological significance of the NO/cGMP/PKG signaling pathway, emphasizing the role of PKG I isozymes in mediating the effects of increased cGMP levels in various physiological and pathological contexts.The article discusses the role of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in cellular signaling, focusing on the cGMP-dependent protein kinase I (PKG I) isozymes. NO, a small gaseous molecule, is synthesized by nitric oxide synthases (NOS) and acts as a signaling molecule in various physiological processes, including vascular smooth muscle relaxation and platelet aggregation. The production of cGMP from NO is catalyzed by guanylyl cyclases (GCs), which are activated by NO. cGMP levels are regulated by the balance between GCs and cyclic nucleotide phosphodiesterases (PDEs). The article highlights the importance of PKG I isozymes in mediating the effects of increased cGMP levels. PKG I isozymes (PKG Iα and PKG Iβ) are activated by cGMP binding to allosteric sites and undergo autoinhibition in the absence of cGMP. PKG Iα has a higher affinity for cGMP than PKG Iβ, and both isozymes have distinct substrate specificities and subcellular localizations. PKG I isozymes can be localized to specific compartments within cells and can translocate between compartments in response to changes in cGMP levels. The article also discusses the cross-talk between cGMP-dependent protein kinases and cGMP-gated cation channels, as well as the regulation of PKG I by cGMP-hydrolyzing PDEs. The effects of NO-induced increases in cGMP on various cellular processes, such as calcium homeostasis, gene expression, and vasodilation, are reviewed. Additionally, the article explores the therapeutic potential of targeting the NO/cGMP/PKG signaling pathway, including the development of drugs that inhibit PDEs to enhance NO/cGMP signaling. Overall, the article provides a comprehensive overview of the mechanisms and biological significance of the NO/cGMP/PKG signaling pathway, emphasizing the role of PKG I isozymes in mediating the effects of increased cGMP levels in various physiological and pathological contexts.