sGC

Soluble guanylate cyclase (sGC) is a cytosolic enzyme that catalyzes the conversion of GTP to cyclic GMP (cGMP). It functions as a receptor for nitric oxide (NO) and typically forms a heterodimer composed of one alpha subunit and one beta subunit, with the alpha subunit encoded by GUCY1A1 (and related isoforms) and the beta subunit by GUCY1B1 (and related isoforms). Additional tissue-specific alpha and beta isoforms have been described.

NO activates sGC by binding to the ferrous heme moiety in the beta subunit, triggering a conformational change that enhances the catalytic formation of cGMP. The produced cGMP then activates protein kinase G (PKG), modulates ion channels, and influences phosphodiesterases, leading to physiological effects such as smooth muscle relaxation and vasodilation, as well as roles in neurotransmission and platelet function.

sGC activity is influenced by the redox state of its heme group. Oxidative stress can oxidize or displace the heme, reducing NO responsiveness. Pharmacological modulators include sGC stimulators, such as riociguat, which directly stimulate sGC and increase sensitivity to NO, and sGC activators, such as cinaciguat, which activate oxidized or heme-free sGC.

Physiological and clinical relevance centers on vascular tone regulation, platelet aggregation inhibition, and nervous system signaling. Dysregulation of sGC-cGMP signaling is linked to hypertension, heart failure, and pulmonary arterial hypertension. Therapeutic agents targeting sGC have been developed for PAH and heart failure, with ongoing research into broader applications and tissue-specific effects.

Structure and genetics: sGC is a cytosolic heterodimer with catalytic and regulatory domains. The genes GUCY1A1 and GUCY1B1 encode the canonical alpha and beta subunits, respectively, with additional isoforms (e.g., GUCY1A2, GUCY1B2) reported in specific tissues.