# Gasotransmitter

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Class of neurotransmitters

**Gasotransmitters** is a class of [neurotransmitters](/source/Neurotransmitter). The molecules are distinguished from other bioactive endogenous [gaseous signaling molecules](/source/Gaseous_signaling_molecules) based on a need to meet distinct characterization criteria. Currently, only [nitric oxide](/source/Nitric_oxide), [carbon monoxide](/source/Carbon_monoxide), and [hydrogen sulfide](/source/Hydrogen_sulfide) are accepted as gasotransmitters.[1] According to in vitro models, gasotransmitters, like other gaseous signaling molecules, may bind to [gasoreceptors](/source/Gas_sensor_protein) and trigger signaling in the cells.[1]

The name gasotransmitter is not intended to suggest a gaseous [physical state](/source/Physical_state) such as [infinitesimally](/source/Infintesimal) small gas [bubbles](/source/Decompression_sickness); the physical state is [dissolution](/source/Dissolution_(chemistry)) in complex [body fluids](/source/Body_fluid) and [cytosol](/source/Cytosol).[2] These particular gases share many common features in their production and function but carry on their tasks in unique ways which differ from classical signaling molecules.

## Criteria

The terminology and characterization criteria of "gasotransmitter" were first introduced in 2002.[3] For one gas molecule to be categorized as a gasotransmitter, all of the following criteria should be met.[4][3]

1. It is a small molecule of gas;

1. It is freely permeable to membranes. As such, its effects do not rely on the cognate membrane receptors. It can have endocrine, paracrine, and autocrine effects. In their endocrine mode of action, for example, gasotransmitters can enter the blood stream; be carried to remote targets by scavengers and released there, and modulate functions of remote target cells;

1. It is endogenously and enzymatically generated and its production is regulated;

1. It has well defined and specific functions at physiologically relevant concentrations. Thus, manipulating the endogenous levels of this gas evokes specific physiological changes;

1. Functions of this endogenous gas can be mimicked by its exogenously applied counterpart;

1. Its cellular effects may or may not be mediated by second messengers, but should have specific cellular and molecular targets.

## Overview

Three candidate gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide, have ironically been discarded as useless toxic gases throughout history. These molecules are a classic example of dose-dependent [hormesis](/source/Hormesis) such that low-dose is beneficial whereas absence or excessive dosing is toxic.

The three gases have similar features and, in theory, participate in shared signaling pathways, although their actions can either be synergistic or antagonistic.[5][6] Nitric oxide and hydrogen sulfide are highly reactive with numerous molecular targets, whereas carbon monoxide is relatively stable and metabolically inert predominately limited to interacting with ferrous ion complexes within mammalian organisms.[7] The scope of biological functions are different across biological systems.[8][9]

Gasotransmitters are under investigation in disciplines such as: [biosensing](/source/Biosensing),[10][11] immunology,[12][13] neuroscience,[14][15] gastroenterology,[16][17][18] and many other fields to include pharmaceutical development initiatives.[19][20][21] While biomedical research has received the most attention, gasotransmitters are under investigation throughout biological systems.[22][23][24][25] Many analytical tools have been developed to study gasotransmitters in vitro.[26]

## Nitric oxide

Main article: [Biological functions of nitric oxide](/source/Biological_functions_of_nitric_oxide)

The 1998 [Nobel Prize in Physiology or Medicine](/source/Nobel_Prize_in_Physiology_or_Medicine) was awarded for the discovery of nitric oxide (NO) as an endogenous signaling molecule. The research emerged in 1980 when NO was first known as the '[endothelium-derived relaxing factor](/source/Endothelium-derived_relaxing_factor)' (EDRF). The identity of EDRF as actually being NO was revealed in 1986 which many consider to mark the beginning of the modern era of gasotransmitter research.[27]

Relative to carbon monoxide and hydrogen sulfide, NO is exceptional due to the fact it is a radical gas.[28] NO is highly reactive (having a lifetime of a few seconds), yet diffuses freely across membranes. These attributes make NO ideal for a transient [paracrine](/source/Paracrine) (between adjacent cells) and [autocrine](/source/Autocrine) (within a single cell) signaling molecule.

It is a known bioproduct in almost all types of organisms, ranging from bacteria to plants, fungi, and animal cells.[29][30] NO is biosynthesized endogenously from [L-arginine](/source/L-arginine) by various [nitric oxide synthase](/source/Nitric_oxide_synthase) (NOS) [enzymes](/source/Enzyme). Reduction of inorganic nitrate may also serve to make NO. Independent of NOS, an alternative pathway coined the nitrate-nitrite-nitric oxide pathway, elevates NO through the sequential reduction of dietary nitrate derived from plant-based foods such as: leafy greens, such as [spinach](/source/Spinach) and [arugula](/source/Arugula), and [beetroot](/source/Beetroot).[31][32][33] For the human body to generate NO through the nitrate-nitrite-nitric oxide pathway, the reduction of nitrate to nitrite occurs in the mouth by the [oral microbiome](/source/Oral_microbiome).[34]

The production of NO is elevated in populations living at high altitudes, which helps these people avoid [hypoxia](/source/Hypoxia_(medical)) by aiding in pulmonary vasculature [vasodilation](/source/Vasodilation). The [endothelium](/source/Endothelium) (inner lining) of [blood vessels](/source/Blood_vessel) uses NO to signal the surrounding [smooth muscle](/source/Smooth_muscle) to relax, thus resulting in [vasodilation](/source/Vasodilation) and increasing blood flow.[35] NO contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Humans with [atherosclerosis](/source/Atherosclerosis), [diabetes](/source/Diabetes), or [hypertension](/source/Hypertension) often show impaired NO pathways.[36] In the context of hypertension, the vasodilatory mechanism follows: NO acts through the stimulation of the soluble guanylate cyclase, which is a heterodimeric enzyme with subsequent formation of cyclic-GMP. Cyclic-GMP activates [protein kinase G](/source/Protein_kinase_G), which causes reuptake of Ca2+ and the opening of calcium-activated potassium channels. The fall in concentration of Ca2+ ensures that the myosin light-chain kinase (MLCK) can no longer phosphorylate the myosin molecule, thereby stopping the crossbridge cycle and leading to relaxation of the smooth muscle cell.[37]

NO is also generated by phagocytes ([monocytes](/source/Monocyte), [macrophages](/source/Macrophage), and [neutrophils](/source/Neutrophil)) as part of the human [immune response](/source/Immune_response).[38] Phagocytes are armed with inducible nitric oxide synthase (iNOS), which is activated by [interferon-gamma](/source/Interferon-gamma) (IFN-γ) as a single signal or by [tumor necrosis factor](/source/Tumor_necrosis_factor) (TNF) along with a second signal.[39][40][41] On the other hand, [transforming growth factor-beta](/source/Transforming_growth_factor-beta) (TGF-β) provides a strong inhibitory signal to iNOS, whereas [interleukin](/source/Interleukin)-4 (IL-4) and IL-10 provide weak inhibitory signals. In this way, the immune system may regulate the resources of phagocytes that play a role in inflammation and immune responses.[42] NO is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites, including *[Leishmania](/source/Leishmania)*[43] and [malaria](/source/Malaria);[44][45][46] the mechanism for this includes DNA damage[47][48][49] and degradation of iron sulfur centers into iron ions and [iron-nitrosyl](/source/Metal_nitrosyl) compounds.[50]

Two important biological reaction mechanisms of NO are S-[nitrosation](/source/Nitrosation) of thiols, and nitrosylation of transition metal ions. S-nitrosation involves the (reversible) conversion of [thiol](/source/Thiol) groups, including [cysteine](/source/Cysteine) residues in proteins, to form S-nitrosothiols (RSNOs). S-[Nitrosation](/source/Nitrosation) is a mechanism for dynamic, post-translational regulation of most or all major classes of protein.[51] The second mechanism, nitrosylation, involves the binding of NO to a transition metal ion like iron to modulate the normal enzymatic activity of an enzyme such as [cytochrome P450](/source/Cytochrome_P450). Nitrosylated ferrous iron is particularly stable, as the binding of the nitrosyl ligand to ferrous iron (Fe(II)) is very strong. Hemoglobin is a prominent example of a heme protein that may be modified by NO by multiple pathways.[52]

There are several mechanisms by which NO has been demonstrated to affect the biology of living cells. These include oxidation of iron-containing proteins such as [ribonucleotide reductase](/source/Ribonucleotide_reductase) and [aconitase](/source/Aconitase), activation of the soluble [guanylate cyclase](/source/Guanylate_cyclase), ADP ribosylation of proteins, protein sulfhydryl group [nitrosylation](/source/Nitrosylation), and iron regulatory factor activation.[53] NO has been demonstrated to activate [NF-κB](/source/NF-%CE%BAB) in peripheral blood mononuclear cells, an important transcription factor in iNOS gene expression in response to inflammation.[54]

## Carbon monoxide

Further information: [Carbon monoxide-releasing molecules](/source/Carbon_monoxide-releasing_molecules)

Carbon monoxide (CO) is produced naturally throughout phylogenetic kingdoms. In mammalian physiology, CO is an important neurotransmitter with beneficial roles such as reducing inflammation and [blood vessel relaxation](/source/Vasodilation).[55][56][57] Mammals maintain a baseline [carboxyhemoglobin](/source/Carboxyhemoglobin) level even if they do not breathe any CO fumes.

In mammals, CO is produced through many enzymatic and non-enzymatic pathways. The most extensively studied source is the catabolic action of [heme oxygenase](/source/Heme_oxygenase) (HMOX) which has been estimated to account for 86% of endogenous CO production. Other contributing sources include: the microbiome, [cytochrome P450 reductase](/source/Cytochrome_P450_reductase), human [acireductone dioxygenase](/source/Acireductone_dioxygenase), [tyrosinase](/source/Tyrosinase), [lipid peroxidation](/source/Lipid_peroxidation), [alpha-keto acids](/source/Alpha-keto_acid), and other oxidative mechanisms. Similarly, the velocity and catalytic activity of HMOX can be enhanced by a plethora of dietary substances and xenobiotics to increase CO production.[8]

The biomedical study of CO traces back to [factitious airs](/source/Factitious_airs) in the 1790s when [Thomas Beddoes](/source/Thomas_Beddoes), [James Watt](/source/James_Watt), [James Lind](/source/James_Lind_(naturalist)), and many others investigated beneficial effects of [hydrocarbonate (water gas)](/source/Hydrocarbonate_(gas)) inhalation.[58] Following [Solomon Snyder's](/source/Solomon_H._Snyder) first report that CO is a normal neurotransmitter in 1993,[59][60] CO has received significant clinical attention as a biological regulator. Unlike NO and H 2S, CO is an inert molecule with remarkable chemical stability capable of diffusing through membranes to exert its effects locally and in distant tissues.[61] CO has been shown to interact with molecular targets including [soluble guanylyl cyclase](/source/Soluble_guanylyl_cyclase), mitochondrial oxidases, [catalase](/source/Catalase), [nitric oxide synthase](/source/Nitric_oxide_synthase), [mitogen-activated protein kinase](/source/Mitogen-activated_protein_kinase), [PPAR gamma](/source/PPAR_gamma), [HIF1A](/source/HIF1A), [NRF2](/source/NRF2), [ion channels](/source/Ion_channel), [cystathionine beta synthase](/source/Cystathionine_beta_synthase), and numerous other functionalities.[62] It is widely accepted that CO primarily exerts its effects in mammals primarily through interacting with [ferrous ion](/source/Iron(II)) complexes such as the [prosthetic](/source/Prosthetic_group) [heme](/source/Heme) moiety of [hemoproteins](/source/Hemoprotein).[7] Aside from Fe2+ interactions, CO may also interact with zinc within metalloproteinases, non-metallic histidine residues of certain ion channels, and various other metallic targets such nickel and molybdenum.[8]

## Hydrogen sulfide

Main article: [Biological functions of hydrogen sulfide](/source/Biological_functions_of_hydrogen_sulfide)

Hydrogen sulfide (H 2S) has important signaling functions in mammalian physiology.[63] The gas is produced [enzymatically](/source/Enzyme) by [cystathionine beta-synthase](/source/Cystathionine_beta-synthase) and [cystathionine gamma-lyase](/source/Cystathionine_gamma-lyase), endogenous non-enzymatic reactions,[64] and may also be produced by the [microbiome](/source/Human_microbiome).[65] Eventually the gas is converted to sulfite in the [mitochondria](/source/Mitochondria) by thiosulfate reductase, and the sulfite is further oxidized to [thiosulfate](/source/Thiosulfate) and [sulfate](/source/Sulfate) by [sulfite oxidase](/source/Sulfite_oxidase). The sulfates are excreted in the urine.[66]

H 2S acts as a relaxant of [smooth muscle](/source/Smooth_muscle) and as a [vasodilator](/source/Vasodilator).[67] Though both NO and H 2S have been shown to relax blood vessels, their mechanisms of action are different: while NO activates the enzyme [guanylyl cyclase](/source/Guanylyl_cyclase), H 2S activates [ATP-sensitive potassium channels](/source/ATP-sensitive_potassium_channel) in smooth muscle cells. Researchers are not clear how the vessel-relaxing responsibilities are shared between NO and H 2S. However, there exists some evidence to suggest that NO does most of the vessel-relaxing work in large vessels and H 2S is responsible for similar action in smaller blood vessels.[68] H 2S deficiency can be detrimental to the vascular function after an [acute myocardial infarction](/source/Myocardial_infarction) (AMI). H 2S therapy reduces myocardial injury and reperfusion complications.[69][70] Due to its effects similar to NO (without its potential to form [peroxides](/source/Peroxides) by interacting with [superoxide](/source/Superoxide)), H 2S is now recognized as potentially protecting against cardiovascular disease.[67][71]

Recent findings suggest strong cellular crosstalk of NO and H 2S,[72] demonstrating that the vasodilatatory effects of these two gases are mutually dependent. Additionally, H 2S reacts with intracellular [S-nitrosothiols](/source/S-Nitrosothiol) to form the smallest S-nitrosothiol (HSNO), and a role of H 2S in controlling the intracellular S-nitrosothiol pool has been suggested.[73]

## Gasotransmitter candidates

Some [gaseous signaling molecules](/source/Gaseous_signaling_molecules) may be a gasotransmitter, notably [methane](/source/Methane) and [cyanide](/source/Cyanide).[74][75] There is ongoing controversy about the strict criteria for gasotransmitters. Some researchers have proposed use of the term *small molecule signaling agent*, while others have proposed to relax the criteria to include other gases, such as [oxygen](/source/Oxygen) as an essential gasotransmitter, similar to that of [essential amino acids](/source/Essential_amino_acid).[76]

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## External links

- [European Network on Gasotransmitters (ENOG)](http://www.gasotransmitters.eu/)

v t e Neurotransmitters Amino acid-derived Major excitatory / inhibitory systems Glutamate system Agmatine Aspartic acid (aspartate) Glutamic acid (glutamate) Glutathione Glycine GSNO GSSG Kynurenic acid NAA NAAG Proline Serine GABA system GABA GABOB GHB Glycine system α-Alanine β-Alanine Glycine Hypotaurine Proline Sarcosine Serine Taurine GHB system GHB T-HCA (GHC) Biogenic amines Monoamines 6-OHM Dopamine Epinephrine (adrenaline) NAS (normelatonin) Norepinephrine (noradrenaline) Serotonin (5-HT) Trace amines 3-Iodothyronamine N-Methylphenethylamine N-Methyltryptamine m-Octopamine p-Octopamine Phenylethanolamine Phenethylamine Synephrine Tryptamine m-Tyramine p-Tyramine Others Histamine Neuropeptides See here instead. Lipid-derived Endocannabinoids 2-AG 2-AGE (noladin ether) 2-ALPI 2-OG AA-5-HT Anandamide (AEA) DEA LPI NADA NAGly OEA Oleamide PEA RVD-Hpα SEA Virodhamine (O-AEA) Neurosteroids See here instead. Nucleobase-derived Nucleosides Adenosine system ADP AMP ATP Vitamin-derived Miscellaneous Cholinergic system Acetylcholine Gasotransmitters Carbon monoxide (CO) Hydrogen sulfide (H2S) Nitric oxide (NO) Candidates Acetaldehyde Ammonia (NH3) Carbonyl sulfide (COS) Nitrous oxide (N2O) Sulfur dioxide (SO2)

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Adapted from the Wikipedia article [Gasotransmitter](https://en.wikipedia.org/wiki/Gasotransmitter) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Gasotransmitter?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.