Cyclic nucleotide

cAMP and cGMP are currently the most well documented cyclic nucleotides, however there is evidence that cCMP (with cytosine) is also involved in eukaryotic cellular messaging.

Discovery of cyclic nucleotides has contributed greatly to the understanding of kinase and phosphatase mechanisms, as well as protein regulation in general.

[1] A number of incremental but important discoveries through the 1950s added to their research, primarily focusing on the activity of glycogen phosphorylase in dog liver.

[2] Earl Sutherland investigated the effect of the hormones adrenaline and glucagon on glycogen phosphorylase, earning him the Nobel Prize in Physiology or Medicine in 1971.

[1] The “active factor” that the hormones produced[2] was finally purified in 1958, and then identified as containing a ribose, a phosphate, and an adenine in equal ratios.

[1] Evgeny Fesenko, Stanislav Kolesnikov, and Arkady Lyubarsky discovered in 1985 that cyclic guanosine monophosphate (cGMP) can initiate the photoresponse in rods.

Soon after, the role of cNMP in gated ion channels of chemosensitive cilia of olfactory sensory neurons was reported by Tadashi Nakamura and Geoffrey Gold.

In 1992 Lawrence Haynes and King-Wai Yau uncovered cNMP’s role in the light-dependent cyclic-nucleotide-gated channel of cone photoreceptors.

[2] Adenylyl cyclase has been found in both a transmembrane and cytosolic form, representing distinct protein classes and different sources of cAMP.

[1] A highly conserved cyclic nucleotide-binding domain (CNB) is present in all proteins that bind cNMPs, regardless of their biological function.

The receptor changes conformation and transmits a signal that activates an enzyme in the cell membrane interior called adenylyl cyclase.

[5] They also facilitate relaxation of smooth muscle cells in vascular tissue,[22] and activate cyclic CNG channels in retinal photoreceptors and olfactory sensory neurons.

[3] Examples of disruptions of cNMP pathways include: mutations in CNG channel genes are associated with degeneration of the retina and with color blindness;[3] and overexpression of cytosolic or soluble adenylyl cyclase (sAC) has been linked to human prostate carcinoma.

Inhibition of sAC, or knockdown by RNA interference (RNAi) transfection has been shown to prevent the proliferation of the prostate carcinoma cells.

Caffeine is a known PDE inhibitor, while drugs used for the treatment of erectile dysfunction like sildenafil and tadalafil also act through inhibiting the activity of phosphodiesterases.