cGMP

cGMP, or cyclic guanosine monophosphate, is a cyclic nucleotide that serves as a second messenger in various signal transduction pathways. It is synthesized from GTP by guanylate cyclases. There are two main classes: soluble guanylate cyclase (sGC), which is a cytosolic enzyme activated by nitric oxide (NO) and other gasotransmitters; and membrane-bound, particulate guanylate cyclase (pGC), which is activated by natriuretic peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). cGMP is degraded mainly by phosphodiesterases, especially PDE5, PDE6, and PDE9, converting it to the inactive 5'-GMP.

As a second messenger, cGMP activates protein kinase G (PKG), which phosphorylates numerous targets, leading to smooth muscle relaxation, decreased intracellular Ca2+, and changes in ion channel activity. In vascular smooth muscle, this pathway mediates NO-induced vasodilation. In photoreceptor cells of the retina, cGMP regulates cGMP-gated cation channels, essential for phototransduction. cGMP also modulates platelet function and cell proliferation in some contexts.

Pharmacological manipulation of cGMP signaling has therapeutic applications. PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil raise cGMP levels to promote vasodilation and are used to treat erectile dysfunction and pulmonary arterial hypertension. NO donors and sGC stimulators (for example, riociguat) increase cGMP production. Alterations in cGMP signaling are also implicated in cardiovascular diseases, glaucoma, and certain retinal disorders.

Measurement of cGMP levels is used in research and clinical settings to study signaling dynamics. The balance between synthesis and degradation, tissue localization of guanylate cyclases, and the expression of PDEs determine cGMP signaling outcomes in different cell types.