The article discusses the role of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in cellular signaling, focusing on cGMP-dependent protein kinases (PKG), particularly PKG I (PKGI). NO is synthesized by nitric oxide synthases (NOS) and activates guanylyl cyclase, leading to cGMP production. cGMP then activates PKG, which phosphorylates various proteins, modulating cellular functions such as calcium homeostasis, platelet activity, and smooth muscle function. PKGI has two isozymes, PKGIα and PKGIβ, which differ in their cGMP-binding affinity and subcellular localization. PKGIα has a higher affinity for cGMP and is more prevalent in certain cellular compartments, while PKGIβ is more membrane-bound in platelets. Both isozymes are involved in various physiological processes, including vascular smooth muscle relaxation, erectile function, and cardiac protection. The article also explores the regulation of PKGI activity, including autoinhibition, activation by cGMP, and autophosphorylation. PKGI is regulated by various factors, including cGMP levels, intracellular cGMP-binding sites, and interactions with other proteins. The study highlights the importance of PKGI in NO/cGMP signaling and its potential as a therapeutic target for diseases involving vascular dysfunction, hypertension, and other conditions. The article also discusses the role of phosphodiesterases in cGMP breakdown and the impact of cGMP signaling on various cellular processes, including gene regulation, protein function, and cell survival. Overall, the study provides a comprehensive overview of the mechanisms underlying NO/cGMP/PKG signaling and its physiological significance.The article discusses the role of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in cellular signaling, focusing on cGMP-dependent protein kinases (PKG), particularly PKG I (PKGI). NO is synthesized by nitric oxide synthases (NOS) and activates guanylyl cyclase, leading to cGMP production. cGMP then activates PKG, which phosphorylates various proteins, modulating cellular functions such as calcium homeostasis, platelet activity, and smooth muscle function. PKGI has two isozymes, PKGIα and PKGIβ, which differ in their cGMP-binding affinity and subcellular localization. PKGIα has a higher affinity for cGMP and is more prevalent in certain cellular compartments, while PKGIβ is more membrane-bound in platelets. Both isozymes are involved in various physiological processes, including vascular smooth muscle relaxation, erectile function, and cardiac protection. The article also explores the regulation of PKGI activity, including autoinhibition, activation by cGMP, and autophosphorylation. PKGI is regulated by various factors, including cGMP levels, intracellular cGMP-binding sites, and interactions with other proteins. The study highlights the importance of PKGI in NO/cGMP signaling and its potential as a therapeutic target for diseases involving vascular dysfunction, hypertension, and other conditions. The article also discusses the role of phosphodiesterases in cGMP breakdown and the impact of cGMP signaling on various cellular processes, including gene regulation, protein function, and cell survival. Overall, the study provides a comprehensive overview of the mechanisms underlying NO/cGMP/PKG signaling and its physiological significance.