cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

Abstract

Cyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets a variety of downstream effector molecules and, thus, elicits a very broad variety of cellular effects. Its production is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC); both enzymes exist in different isoforms. cGMP-induced effects are regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). Depending on the distribution of sGC and pGC and the formation of ligands, this pathway regulates not only the cardiovascular system but also the kidney, lung, liver, and brain function; in addition, the cGMP pathway is involved in the pathogenesis of fibrosis, inflammation, or neurodegeneration and may also play a role in infectious diseases such as malaria. Moreover, new pharmacological approaches are being developed which target sGC-and pGC-dependent pathways for the treatment of various diseases. Therefore, it is of key interest to understand this pathway from scratch, beginning with the molecular basis of cGMP generation, the structure and function of both guanylyl cyclases and cGMP downstream targets; research efforts also focus on the subsequent signaling cascades, their potential crosstalk, and also the translational and, ultimately, the clinical implications of cGMP modulation. This review tries to summarize the contributions to the "9th International cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications" held in Mainz in 2019. Presented data will be discussed and extended also in light of recent landmark findings and ongoing activities in the field of preclinical and clinical cGMP research.

The role of NO in COVID-19 and potential therapeutic strategies

“…Kinase-G also promotes phosphorylation of protein G in smooth muscle cells, which connects seven regions of transmembrane receptors and phospholipases. It then thereby inhibits ligand-receptor interaction and contractile signal transmission, enhancing relaxation of smooth muscle cells and promoting local blood flow [ 35 , 36 ]. In addition, NO is also involved in the metabolic pathways of nitrosothiol (RSNO).…”

Soluble guanylate cyclase stimulators and their potential use: a patent review

“…In essence, the broad number of compound and use-patent applications in the field of sGC agonists underlines the hope that modulation of cGMP signaling with this unique mode of action holds promise for a broad number of patients in cardiovascular diseases and beyond [94].…”

Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging

“…Phosphodiesterases (PDEs) are responsible for cGMP degradation. Their increase impairs vasodilation and increases stiffness, blood pressure, hypertrophy, and inflammation [4,5]. During aging the metabolic balance turns toward cGMP degradation, and it has been shown that acute inhibition of PDE improves vasodilation in aged blood vessels [6][7][8].…”

“…PDEs form a family of enzymes that degrade the substrates cAMP, cGMP, or both. There are 11 PDE subtype families (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), and each member displays tissue and substrate specificity [9]. PDE5 is expressed in vascular smooth muscle cells (VSMC), where it plays a key role in regulation of cGMP, for which it is substrate-specific.…”