PRKG1 (protein kinase cGMP-dependent 1) is a serine/threonine protein kinase that functions as a central mediator of the nitric oxide (NO)/cGMP signaling pathway. Upon cGMP binding, PRKG1 phosphorylates multiple cellular targets to regulate diverse physiological processes including vascular smooth muscle relaxation, platelet inhibition, and cardiac function. The kinase modulates intracellular calcium through multiple mechanisms: phosphorylating IRAG1 to inhibit IP3-induced calcium release, activating potassium channels (KCNMA1), and inactivating transient receptor potential channels [UniProt]. PRKG1 also phosphorylates RhoA to suppress smooth muscle contraction and regulates vasodilator-stimulated phosphoprotein (VASP) in platelets and smooth muscle. Beyond vascular physiology, PRKG1 influences gene expression and neurological processes including axon guidance and learning [UniProt]. Genetically, PRKG1 variants associate with multiple disease states. Pathogenic variants cause familial thoracic aortic aneurysm (FTAA), with PRKG1 mutations conferring higher risk of type A and B aortic dissection compared to elective surgery 1. Loss-of-function PRKG1 variants contribute to heritable thoracic aortic disease, detected through copy-number variation analysis 2. Conversely, PRKG1 exhibits context-dependent roles in cancer: elevated PRKG1 expression blocks myogenic differentiation in rhabdomyosarcoma and predicts sensitivity to AKT inhibitor ipatasertib 3, while PRKG1-AS1 (an antisense RNA) promotes lung adenocarcinoma proliferation and poor prognosis 4. Additionally, PRKG1 polymorphisms associate with childhood asthma susceptibility through gene-environment interactions 5, and human PRKG1 variants correlate with behavioral phenotypes in foraging tasks 6. Therapeutic targeting via PDE5 inhibitors activating PRKG1 signaling shows promise in mitochondrial disease 7, while PRKG1 inhibition represents a potential strategy for Marfan syndrome aortopathy 8.