cCMP and cUMP: emerging second messengers

• cCMP and cUMP are new second messengers.
• cCMP and cUMP are generated by soluble adenylyl and guanylyl cyclase.
• Pseudomonas aeruginosa ExoY is a nucleotidyl cyclase toxin.
• cCMP and cUMP act via known and unknown effectors.

The cyclic purine nucleotides cAMP and cGMP are established second messengers. By contrast, the existence of the cyclic pyrimidine nucleotides cytidine 3′,5′-cyclic monophosphate (cCMP) and uridine 3′,5′-cyclic monophosphate (cUMP) has been controversial for decades. The recent development of highly sensitive mass spectrometry (MS) methods allowed precise quantitation and unequivocal identification of cCMP and cUMP in cells. Importantly, cCMP and cUMP generators, effectors, cleaving enzymes, and transporters have now been identified. Here, I discuss evidence in support of cCMP and cUMP as bona fide second messengers, the emerging therapeutic implications of cCMP and cUMP signaling, and important unresolved questions for this field.