The role of hydrogen sulfide in cyclic nucleotide signaling

Hydrogen sulfide (H₂S) is recognized as an endogenous gaseous transmitter alongside nitric oxide (NO) and carbon monoxide (CO). By integrating into multiple signaling pathways, H₂S elicits biological functions in various mammalian systems. Among these pathways, cyclic nucleotide signaling has gradually gained attention in the past decade. Based on current evidence, it seems that H₂S may differentially affect the activity of resting adenylyl cyclases (ACs) and activated ACs, therefore playing a dual role in the regulation of cyclic adenosine monophosphate (cAMP) mediated signaling. However, how H₂S achieves the differential regulation on ACs remains unknown at molecular level. In the context of cyclic guanosine monophosphate (cGMP) regulation, H₂S augments its downstream signaling at least through three different mechanisms: (1) H₂S potentiates the response of soluble guanylyl cyclases (sGCs) to NO; (2) H₂S inhibits activity of phosphodiesterases (PDEs); and (3) H₂S enhances the production of NO. By regulating cyclic nucleotide signaling, H₂S possesses therapeutic potentials particularly for hypertension and cardiac injury which have also been discussed in the current review. Nevertheless, a detailed portrayal of H₂S mediated interaction with target proteins is still required for a better understanding of the role of this important gaseous mediator in regulating cyclic nucleotide signaling.