CGMP signalling: from bench to bedside

Abstract

The 2nd International Conference on cGMP Generators, Effectors and Therapeutic Implications took place in Potsdam, Germany, during 10–12 June 2005, and was organized by L. Ignarro, F. Hofmann, H. Schmidt and J.P. Stasch (www.cyclicgmp.net). The next cGMP meeting will be held in Dresden, Germany, in June 2007. ![][1] Cyclic nucleotide research originated in the 1960s, when cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were first identified as natural products (reviewed in Beavo & Brunton, 2002). The discovery of cAMP led to the formulation of the second‐messenger concept in hormone signalling by Earl W. Sutherland, who was duly rewarded with the Nobel Prize in 1971. Consequently, cAMP research surged ahead, whereas cGMP attracted little attention. Indeed, the biological role of cGMP was unknown until the 1980s when two key discoveries were made. First, it was found that a peptide synthesized in the heart, atrial natriuretic peptide (ANP), could stimulate cGMP synthesis by binding to a transmembrane receptor, the particulate guanylyl cyclase (pGC). Second, the elusive endothelium‐derived relaxing factor was identified as nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) in smooth muscle cells to synthesize cGMP, thereby causing vasorelaxation. Subsequently, other components of cGMP metabolism and signal transduction were also identified (Fig 1). It is now known that cGMP‐hydrolysing phosphodiesterases (PDEs) are responsible for cGMP breakdown, and at least three types of cGMP‐binding protein transduce the cGMP signal to alter cellular function. These three types are cGMP‐modulated cation channels, cGMP‐dependent protein kinases (cGKs) and cGMP‐regulated PDEs that degrade cAMP and/or cGMP. Figure 1. Current concepts of cGMP signalling. cGMP generators (green) and effectors (red), as well as some downstream pathways and cellular functions (grey boxes) that are involved in the effects of endogenous cGMP and/or cGMP‐elevating drugs (blue), are shown. The lower part shows some current (blue) as well as potential … [1]: /embed/graphic-1.gif