Gasotransmitters

Gasotransmitters are a class of endogenous gaseous signaling molecules that are produced within the body and readily cross cell membranes to affect nearby or distant cells without the need for membrane receptors. The canonical gasotransmitters are nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). They function as small, freely diffusible signals that integrate into diverse physiological processes.

Nitric oxide is synthesized by nitric oxide synthase enzymes present in different tissues: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). NO activates soluble guanylate cyclase, increasing cyclic GMP, which mediates vasodilation, neurotransmission, and immune defense. It has a very short half-life and can be cytotoxic at high concentrations, underscoring the need for tight regulation.

Carbon monoxide is produced during the breakdown of heme by heme oxygenases, primarily HO-1 (inducible) and HO-2 (constitutive). CO can also activate guanylate cyclase and influence ion channels, inflammation, and apoptosis. At physiological levels, it contributes to vasodilation and cytoprotection, while excess production can be harmful.

Hydrogen sulfide is generated by enzymes such as cystathionine beta-synthase and cystathionine gamma-lyase, with additional production in mitochondria. H2S modulates signaling through sulfhydration of cysteine residues on proteins, regulates potassium channels and NMDA receptors, and participates in vascular relaxation, neuromodulation, and cellular stress responses.

The three gases interact and influence each other’s production and effects. Dysregulation of gasotransmitter signaling is linked to cardiovascular disease, neurodegeneration, and inflammation. Therapeutic interest includes donors and modulators for NO, CO, and H2S, but clinical application faces challenges related to targeting, safety, and precise measurement.