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.

Keywords: Guanylyl cyclases; Natriuretic peptides; Nitric oxide; Phosphodiesterases; Praliciguat; Riociguat; Vericiguat; cGMP; sGC activators; sGC stimulators.

Fig. 1

ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; cGK, cGMP-dependent protein kinase; cGMP, cyclic guanosine monophosphate; CNG, cyclic nucleotide-gated ion channels; CNP, C-type natriuretic peptide; GTP, guanosine triphosphate; GMP, guanosine monophosphate; NO, nitric oxide; NOS, nitric oxide synthase; NP, natriuretic peptide; PDE, phosphodiesterase; pGC, particulate guanylyl cyclase; PKG, protein kinase G; sGC, soluble guanylyl cyclase

Fig. 2

Participants of the 9th International Conference on cGMP, held in Mainz, Germany, in 2019 from June 14th–16th. For program and meeting information see https://www.cyclicgmp.net/index.html; for abstracts see 10.1186/s12967-019-1994-0 (J Transl Med 2019, 17(Suppl 2):254)