Gasotransmitters: The Lethal Gases Your Body Manufactures as Signals
Nitric oxide, carbon monoxide and hydrogen sulphide — all toxic in quantity, all produced endogenously as signalling molecules. They break the rules for classical signalling: membrane-permeable, needing no surface receptor, unstored, produced on demand and acting directly on metal centres, especially heme iron. The pattern isn't coincidence — the metal-binding chemistry that makes them lethal is what makes them detectable, and so useful as messages.
**Gasotransmitters** are gases produced endogenously by the body and used deliberately as signalling molecules. Three are recognised: **nitric oxide (NO)**, **carbon monoxide (CO)** and **hydrogen sulphide (H₂S)**. All three are toxic at higher concentrations. All three are manufactured on purpose inside cells. The category is a standing illustration that the dose makes the poison. ## What defines the class Gasotransmitters break the rules for classical signalling molecules. They are small, freely membrane-permeable gases — so they need no receptor on the cell surface, are not stored in vesicles, are not released by exocytosis, and are not cleared by reuptake. They are produced on demand by an enzyme, diffuse to their target, act on it directly, and are then consumed or diffuse away. Their targets are typically **metal centres**, especially the iron in heme groups. See Heme Ligand-Switching: How Biological Carbon Monoxide Sensors Work. ## Nitric oxide The first to be recognised, discovered as the endothelium-derived relaxing factor and the subject of the 1998 Nobel Prize in Physiology or Medicine. Produced by nitric oxide synthase, it activates **soluble guanylate cyclase**, raising cGMP and relaxing vascular smooth muscle. Its pharmacology is old and enormous: nitroglycerin for angina has worked through this pathway since the nineteenth century, long before the mechanism was known, and the phosphodiesterase-5 inhibitors used for erectile dysfunction and pulmonary hypertension act by preventing cGMP breakdown. ## Carbon monoxide Produced by **heme oxygenase**, the enzyme that degrades old heme — so every time your body recycles a red blood cell, it liberates CO. This is the source of the 1–3% baseline carboxyhaemoglobin in every non-smoker. CO activates soluble guanylate cyclase like NO, though far more weakly, and modulates ion channels. Its documented effects are vasodilation, neurotransmission, anti-inflammatory action and cytoprotection. It also feeds into the circadian system through the transcription factor NPAS2. ## Hydrogen sulphide Produced by cystathionine β-synthase and related enzymes, acting largely by **persulfidation** of protein cysteine residues, with roles in vasodilation, inflammation and, strikingly, in inducing suspended-animation-like hypometabolic states in some model organisms. ## Why the pattern is not a coincidence All three are highly reactive with, or bind avidly to, metal centres — which is what makes them lethal in quantity, since that is exactly how they poison respiratory enzymes and oxygen transport. It is also what makes them useful as signals: a molecule that binds a metal centre changes the shape of the protein holding it, which is a signal. Evolution repeatedly recruited dangerous small molecules for messaging because the same chemistry that makes them dangerous makes them detectable. The therapeutic implication is being pursued directly — see Carbon Monoxide as Experimental Medicine: Inhaled CO and CORMs.