cGMPs

cGMPs, or cyclic guanosine monophosphates, are a family of cyclic nucleotides that function as intracellular second messengers. They are produced from GTP by guanylyl cyclases and participate in diverse signaling pathways that regulate physiological processes.

There are two main guanylyl cyclase families. Soluble guanylyl cyclases (sGC) are activated by nitric oxide (NO) and other gasotransmitters, while membrane-bound guanylyl cyclases (particulate guanylyl cyclases, pGC) act as receptors for natriuretic peptides such as atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Activation of these enzymes increases intracellular cGMP levels, enabling downstream signaling.

cGMP signals are transduced through several effectors. Protein kinase G (PKG) is a primary serine/threonine kinase target, while cyclic nucleotide-gated (CNG) ion channels and various phosphodiesterases are also regulated by cGMP. The intracellular concentration of cGMP is tightly controlled by phosphodiesterases, which hydrolyze cGMP to 5'-GMP, thereby terminating the signal.

Physiological roles of cGMPs are wide-ranging. They contribute to the regulation of vascular tone and blood pressure through smooth muscle relaxation, influence platelet aggregation, and participate in retinal phototransduction by controlling cGMP-dependent ion channels. They also participate in neuronal signaling and gastrointestinal and other organ functions.

Clinically, the NO-sGC-cGMP pathway is a therapeutic target in cardiovascular disease. PDE5 inhibitors, such as sildenafil, elevate cGMP to promote vasodilation. sGC stimulators, such as riociguat, directly activate sGC. Dysregulation of cGMP signaling is implicated in hypertension, heart failure, and pulmonary arterial hypertension.