gasotransmitter

The terminology and characterization criteria of “gasotransmitter” were first introduced in 2002.{{cite journal | vauthors = Wang R | title = Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? | journal = FASEB Journal | volume = 16 | issue = 13 | pages = 1792–1798 | date = November 2002 | pmid = 12409322 | doi = 10.1096/fj.02-0211hyp | doi-access = free | s2cid = 40765922 }} For one gas molecule to be categorized as a gasotransmitter, all of the following criteria should be met.Wang R (ed) (2004) Signal Transduction and the Gasotransmitters: NO, CO and H₂S in Biology and Medicine. Humana Press, New Jersey, USA.

1. It is a small molecule of gas;
2. 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;
3. It is endogenously and enzymatically generated and its production is regulated;
4. It has well defined and specific functions at physiologically relevant concentrations. Thus, manipulating the endogenous levels of this gas evokes specific physiological changes;
5. Functions of this endogenous gas can be mimicked by its exogenously applied counterpart;
6. Its cellular effects may or may not be mediated by second messengers, but should have specific cellular and molecular targets.

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 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.{{cite journal | vauthors = Wang R | title = Shared signaling pathways among gasotransmitters | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 23 | pages = 8801–2 | date = June 2012 | pmid = 22615409 | doi = 10.1073/pnas.1206646109 | pmc = 3384202 | bibcode = 2012PNAS..109.8801W | doi-access = free }}{{cite journal | vauthors = Hendriks KD, Maassen H, van Dijk PR, Henning RH, van Goor H, Hillebrands JL | title = Gasotransmitters in health and disease: a mitochondria-centered view | journal = Current Opinion in Pharmacology | volume = 45 | pages = 87–93 | date = April 2019 | pmid = 31325730 | doi = 10.1016/j.coph.2019.07.001 | s2cid = 198135525 | doi-access = free }} 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.{{cite journal | vauthors = Motterlini R, Foresti R | title = Biological signaling by carbon monoxide and carbon monoxide-releasing molecules | journal = American Journal of Physiology. Cell Physiology | volume = 312 | issue = 3 | pages = C302–C313 | date = March 2017 | pmid = 28077358 | doi = 10.1152/ajpcell.00360.2016 | s2cid = 21861993 | doi-access = free }} The scope of biological functions are different across biological systems.{{cite journal | vauthors = Wareham LK, Southam HM, Poole RK | title = Do nitric oxide, carbon monoxide and hydrogen sulfide really qualify as 'gasotransmitters' in bacteria? | journal = Biochemical Society Transactions | volume = 46 | issue = 5 | pages = 1107–1118 | date = October 2018 | pmid = 30190328 | pmc = 6195638 | doi = 10.1042/BST20170311 }}

Gasotransmitters are under investigation in disciplines such as: biosensing,{{cite journal | vauthors = Shimizu T, Lengalova A, Martínek V, Martínková M | title = Heme: emergent roles of heme in signal transduction, functional regulation and as catalytic centres | journal = Chemical Society Reviews | volume = 48 | issue = 24 | pages = 5624–5657 | date = December 2019 | pmid = 31748766 | doi = 10.1039/C9CS00268E | s2cid = 208217502 }}{{cite journal | vauthors = Shimizu T, Huang D, Yan F, Stranava M, Bartosova M, Fojtíková V, Martínková M | title = Gaseous O2, NO, and CO in signal transduction: structure and function relationships of heme-based gas sensors and heme-redox sensors | journal = Chemical Reviews | volume = 115 | issue = 13 | pages = 6491–6533 | date = July 2015 | pmid = 26021768 | doi = 10.1021/acs.chemrev.5b00018 }} immunology,{{cite journal | vauthors = Campbell NK, Fitzgerald HK, Dunne A | title = Regulation of inflammation by the antioxidant haem oxygenase 1 | journal = Nature Reviews. Immunology | volume = 21 | issue = 7 | pages = 411–425 | date = July 2021 | pmid = 33514947 | doi = 10.1038/s41577-020-00491-x | s2cid = 231762031 }}{{cite journal | vauthors = Fagone P, Mazzon E, Bramanti P, Bendtzen K, Nicoletti F | title = Gasotransmitters and the immune system: Mode of action and novel therapeutic targets | journal = European Journal of Pharmacology | volume = 834 | pages = 92–102 | date = September 2018 | pmid = 30016662 | doi = 10.1016/j.ejphar.2018.07.026 | s2cid = 51679533 }} neuroscience,{{cite journal | vauthors = Siracusa R, Schaufler A, Calabrese V, Fuller PM, Otterbein LE | title = Carbon Monoxide: from Poison to Clinical Trials | journal = Trends in Pharmacological Sciences | volume = 42 | issue = 5 | pages = 329–339 | date = May 2021 | pmid = 33781582 | pmc = 8134950 | doi = 10.1016/j.tips.2021.02.003 }}{{cite journal | vauthors = Singh S | title = Updates on Versatile Role of Putative Gasotransmitter Nitric Oxide: Culprit in Neurodegenerative Disease Pathology | journal = ACS Chemical Neuroscience | volume = 11 | issue = 16 | pages = 2407–2415 | date = August 2020 | pmid = 32564594 | doi = 10.1021/acschemneuro.0c00230 | s2cid = 219973120 }} gastroenterology,{{cite journal | vauthors = Magierowski M, Magierowska K, Kwiecien S, Brzozowski T | title = Gaseous mediators nitric oxide and hydrogen sulfide in the mechanism of gastrointestinal integrity, protection and ulcer healing | journal = Molecules | volume = 20 | issue = 5 | pages = 9099–9123 | date = May 2015 | pmid = 25996214 | doi = 10.3390/molecules20059099 | pmc = 6272495 | doi-access = free }}{{cite journal | vauthors = Liu T, Mukosera GT, Blood AB | title = The role of gasotransmitters in neonatal physiology | journal = Nitric Oxide | volume = 95 | pages = 29–44 | date = February 2020 | pmid = 31870965 | pmc = 7241003 | doi = 10.1016/j.niox.2019.12.002 }}{{cite journal | vauthors = Gibbons SJ, Verhulst PJ, Bharucha A, Farrugia G | title = Review article: carbon monoxide in gastrointestinal physiology and its potential in therapeutics | journal = Alimentary Pharmacology & Therapeutics | volume = 38 | issue = 7 | pages = 689–702 | date = October 2013 | pmid = 23992228 | pmc = 3788684 | doi = 10.1111/apt.12467 }} and many other fields to include pharmaceutical development initiatives.{{cite journal | vauthors = Motterlini R, Otterbein LE | title = The therapeutic potential of carbon monoxide | journal = Nature Reviews. Drug Discovery | volume = 9 | issue = 9 | pages = 728–743 | date = September 2010 | pmid = 20811383 | doi = 10.1038/nrd3228 | s2cid = 205477130 }}{{cite journal | vauthors = Wallace JL, Wang R | title = Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter | journal = Nature Reviews. Drug Discovery | volume = 14 | issue = 5 | pages = 329–345 | date = May 2015 | pmid = 25849904 | doi = 10.1038/nrd4433 | s2cid = 5361233 }}{{cite journal | vauthors = Papapetropoulos A, Foresti R, Ferdinandy P | title = Pharmacology of the 'gasotransmitters' NO, CO and H2S: translational opportunities | journal = British Journal of Pharmacology | volume = 172 | issue = 6 | pages = 1395–1396 | date = March 2015 | pmid = 25891246 | pmc = 4369252 | doi = 10.1111/bph.13005 }} While biomedical research has received the most attention, gasotransmitters are under investigation throughout biological systems.{{cite journal | vauthors = Imbrogno S, Filice M, Cerra MC, Gattuso A | title = NO, CO and H₂ S: What about gasotransmitters in fish and amphibian heart? | journal = Acta Physiologica | volume = 223 | issue = 1 | pages = e13035 | date = May 2018 | pmid = 29338122 | doi = 10.1111/apha.13035 | s2cid = 4793586 }}{{Cite journal| vauthors = Kolupaev YE, Karpets YV, Beschasniy SP, Dmitriev AP |date=2019-09-01|title=Gasotransmitters and Their Role in Adaptive Reactions of Plant Cells |journal=Cytology and Genetics|language=en|volume=53|issue=5|pages=392–406|doi=10.3103/S0095452719050098|s2cid=208605375|issn=1934-9440}}{{cite journal | vauthors = Tift MS, Alves de Souza RW, Weber J, Heinrich EC, Villafuerte FC, Malhotra A, Otterbein LE, Simonson TS | title = Adaptive Potential of the Heme Oxygenase/Carbon Monoxide Pathway During Hypoxia | journal = Frontiers in Physiology | volume = 11 | pages = 886 | date = 2020-07-22 | pmid = 32792988 | pmc = 7387684 | doi = 10.3389/fphys.2020.00886 | doi-access = free }}{{cite journal | vauthors = Oleskin AV, Shenderov BA | title = Neuromodulatory effects and targets of the SCFAs and gasotransmitters produced by the human symbiotic microbiota | journal = Microbial Ecology in Health and Disease | volume = 27 | pages = 30971 | date = 2016-07-05 | pmid = 27389418 | pmc = 4937721 | doi = 10.3402/mehd.v27.30971 }} Many analytical tools have been developed to study gasotransmitters in vitro.{{cite book| vauthors = Peng H, Chen W, Wang B | chapter = Methods for the Detection of Gasotransmitters|date=July 2012| title = Gasotransmitters: Physiology and Pathophysiology|pages=99–137| veditors = Hermann A, Sitdikova GF, Weiger TM |place=Berlin, Heidelberg|publisher=Springer|language=en|doi=10.1007/978-3-642-30338-8_4|isbn=978-3-642-30338-8 }}

{{Main|Biological functions of nitric oxide}}

The 1998 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' (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.{{cite journal | vauthors = Yang XX, Ke BW, Lu W, Wang BH | title = CO as a therapeutic agent: discovery and delivery forms | journal = Chinese Journal of Natural Medicines | volume = 18 | issue = 4 | pages = 284–295 | date = April 2020 | pmid = 32402406 | doi = 10.1016/S1875-5364(20)30036-4 | s2cid = 218635089}}

Relative to carbon monoxide and hydrogen sulfide, NO is exceptional due to the fact it is a radical gas.{{Cite journal | vauthors = Mir JM, Maurya RC |date=2018-12-19|title=A gentle introduction to gasotransmitters with special reference to nitric oxide: biological and chemical implications|url=https://www.degruyter.com/document/doi/10.1515/revic-2018-0011/html|journal=Reviews in Inorganic Chemistry|volume=38|issue=4|pages=193–220|doi=10.1515/revic-2018-0011|s2cid=105481514|issn=2191-0227}} 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 (between adjacent cells) and 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.{{cite book | vauthors = Rőszer T |title=The biology of subcellular nitric oxide |date=2012 |publisher=Springer Science+Business Media B.V |location=Dordrecht |isbn=978-94-007-2818-9}}{{cite journal | vauthors = Kolbert Z, Barroso JB, Brouquisse R, Corpas FJ, Gupta KJ, Lindermayr C, Loake GJ, Palma JM, Petřivalský M, Wendehenne D, Hancock JT | title = A forty year journey: The generation and roles of NO in plants | journal = Nitric Oxide | volume = 93 | pages = 53–70 | date = December 2019 | pmid = 31541734 | doi = 10.1016/j.niox.2019.09.006 | s2cid = 202718340 | url = https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=56974 }} NO is biosynthesized endogenously from L-arginine by various nitric oxide synthase (NOS) enzymes. 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 and arugula, and beetroot.{{cite web|title=Plant-based Diets | Plant-based Foods | Beetroot Juice | Nitric Oxide Vegetables|url=http://www.berkeleytest.com/plant-based.html|url-status=dead|archive-url=https://web.archive.org/web/20131004222229/http://www.berkeleytest.com/plant-based.html|archive-date=2013-10-04|access-date=2013-10-04|publisher=Berkeley Test}}{{cite journal | vauthors = Ghosh SM, Kapil V, Fuentes-Calvo I, Bubb KJ, Pearl V, Milsom AB, Khambata R, Maleki-Toyserkani S, Yousuf M, Benjamin N, Webb AJ, Caulfield MJ, Hobbs AJ, Ahluwalia A | title = Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential | journal = Hypertension | volume = 61 | issue = 5 | pages = 1091–1102 | date = May 2013 | pmid = 23589565 | doi = 10.1161/HYPERTENSIONAHA.111.00933 | doi-access = free }}{{cite journal | vauthors = Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, Deanfield J, Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A | title = Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite | journal = Hypertension | volume = 51 | issue = 3 | pages = 784–790 | date = March 2008 | pmid = 18250365 | pmc = 2839282 | doi = 10.1161/HYPERTENSIONAHA.107.103523 }} 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.{{cite journal | vauthors = Hezel MP, Weitzberg E | title = The oral microbiome and nitric oxide homoeostasis | journal = Oral Diseases | volume = 21 | issue = 1 | pages = 7–16 | date = January 2015 | pmid = 23837897 | doi = 10.1111/odi.12157 | doi-access = free }}

The production of NO is elevated in populations living at high altitudes, which helps these people avoid hypoxia by aiding in pulmonary vasculature vasodilation. The endothelium (inner lining) of blood vessels uses NO to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow.{{cite journal | vauthors = Cirino G, Vellecco V, Bucci M | title = Nitric oxide and hydrogen sulfide: the gasotransmitter paradigm of the vascular system | journal = British Journal of Pharmacology | volume = 174 | issue = 22 | pages = 4021–4031 | date = November 2017 | pmid = 28407204 | pmc = 5660007 | doi = 10.1111/bph.13815 }} NO contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Humans with atherosclerosis, diabetes, or hypertension often show impaired NO pathways.{{cite journal| vauthors = Dessy C, Feron O |year=2004 |title= Pathophysiological Roles of Nitric Oxide: In the Heart and the Coronary Vasculature|journal=Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents|volume=3|issue=3|pages=207–216|doi=10.2174/1568014043355348}} 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, 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.{{cite journal | vauthors = James NT, Meek GA | title = Studies on the lipid content of pigeon breast muscle | journal = Comparative Biochemistry and Physiology. A, Comparative Physiology | volume = 53 | issue = 1 | pages = 105–107 | date = January 1976 | pmid = 174 | doi = 10.1016/s0300-9629(76)80020-5 }}

NO is also generated by phagocytes (monocytes, macrophages, and neutrophils) as part of the human immune response.{{cite journal | vauthors = Green SJ, Mellouk S, Hoffman SL, Meltzer MS, Nacy CA | title = Cellular mechanisms of nonspecific immunity to intracellular infection: cytokine-induced synthesis of toxic nitrogen oxides from L-arginine by macrophages and hepatocytes | journal = Immunology Letters | volume = 25 | issue = 1–3 | pages = 15–19 | date = August 1990 | pmid = 2126524 | doi = 10.1016/0165-2478(90)90083-3 | url = https://zenodo.org/record/1258353 }} Phagocytes are armed with inducible nitric oxide synthase (iNOS), which is activated by interferon-gamma (IFN-γ) as a single signal or by tumor necrosis factor (TNF) along with a second signal.{{cite book | vauthors = Gorczynski RM, Stanley J |title=Clinical immunology |date=1999 |publisher=Landes Bioscience |location=Austin, TX |isbn=978-1-57059-625-4}}{{cite journal | vauthors = Green SJ, Nacy CA, Schreiber RD, Granger DL, Crawford RM, Meltzer MS, Fortier AH | title = Neutralization of gamma interferon and tumor necrosis factor alpha blocks in vivo synthesis of nitrogen oxides from L-arginine and protection against Francisella tularensis infection in Mycobacterium bovis BCG-treated mice | journal = Infection and Immunity | volume = 61 | issue = 2 | pages = 689–698 | date = February 1993 | pmid = 8423095 | pmc = 302781 | doi = 10.1128/IAI.61.2.689-698.1993 }}{{cite journal | vauthors = Kamijo R, Gerecitano J, Shapiro D, Green SJ, Aguet M, Le J, Vilcek J | title = Generation of nitric oxide and clearance of interferon-gamma after BCG infection are impaired in mice that lack the interferon-gamma receptor | journal = Journal of Inflammation | volume = 46 | issue = 1 | pages = 23–31 | year = 1995 | pmid = 8832969 }} On the other hand, transforming growth factor-beta (TGF-β) provides a strong inhibitory signal to iNOS, whereas 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.{{cite journal | vauthors = Green SJ, Scheller LF, Marletta MA, Seguin MC, Klotz FW, Slayter M, Nelson BJ, Nacy CA | title = Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens | journal = Immunology Letters | volume = 43 | issue = 1–2 | pages = 87–94 | date = December 1994 | pmid = 7537721 | doi = 10.1016/0165-2478(94)00158-8 | hdl-access = free | hdl = 2027.42/31140 }} NO is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites, including Leishmania{{cite journal | vauthors = Green SJ, Crawford RM, Hockmeyer JT, Meltzer MS, Nacy CA | title = Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-gamma-stimulated macrophages by induction of tumor necrosis factor-alpha | journal = Journal of Immunology | volume = 145 | issue = 12 | pages = 4290–4297 | date = December 1990 | doi = 10.4049/jimmunol.145.12.4290 | pmid = 2124240 | s2cid = 21034574 }} and malaria;{{cite journal | vauthors = Seguin MC, Klotz FW, Schneider I, Weir JP, Goodbary M, Slayter M, Raney JJ, Aniagolu JU, Green SJ | title = Induction of nitric oxide synthase protects against malaria in mice exposed to irradiated Plasmodium berghei infected mosquitoes: involvement of interferon gamma and CD8+ T cells | journal = The Journal of Experimental Medicine | volume = 180 | issue = 1 | pages = 353–358 | date = July 1994 | pmid = 7516412 | pmc = 2191552 | doi = 10.1084/jem.180.1.353 }}{{cite journal | vauthors = Mellouk S, Green SJ, Nacy CA, Hoffman SL | title = IFN-gamma inhibits development of Plasmodium berghei exoerythrocytic stages in hepatocytes by an L-arginine-dependent effector mechanism | journal = Journal of Immunology | volume = 146 | issue = 11 | pages = 3971–3976 | date = June 1991 | doi = 10.4049/jimmunol.146.11.3971 | pmid = 1903415 | s2cid = 45487458 | doi-access = free }}{{cite journal | vauthors = Klotz FW, Scheller LF, Seguin MC, Kumar N, Marletta MA, Green SJ, Azad AF | title = Co-localization of inducible-nitric oxide synthase and Plasmodium berghei in hepatocytes from rats immunized with irradiated sporozoites | journal = Journal of Immunology | volume = 154 | issue = 7 | pages = 3391–3395 | date = April 1995 | doi = 10.4049/jimmunol.154.7.3391 | pmid = 7534796 | s2cid = 12612236 | doi-access = free }} the mechanism for this includes DNA damage{{cite journal | vauthors = Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS | title = DNA deaminating ability and genotoxicity of nitric oxide and its progenitors | journal = Science | volume = 254 | issue = 5034 | pages = 1001–1003 | date = November 1991 | pmid = 1948068 | doi = 10.1126/science.1948068 | bibcode = 1991Sci...254.1001W }}{{cite journal | vauthors = Nguyen T, Brunson D, Crespi CL, Penman BW, Wishnok JS, Tannenbaum SR | title = DNA damage and mutation in human cells exposed to nitric oxide in vitro | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 7 | pages = 3030–3034 | date = April 1992 | pmid = 1557408 | pmc = 48797 | doi = 10.1073/pnas.89.7.3030 | bibcode = 1992PNAS...89.3030N | doi-access = free }} Free text.{{cite journal | vauthors = Li CQ, Pang B, Kiziltepe T, Trudel LJ, Engelward BP, Dedon PC, Wogan GN | title = Threshold effects of nitric oxide-induced toxicity and cellular responses in wild-type and p53-null human lymphoblastoid cells | journal = Chemical Research in Toxicology | volume = 19 | issue = 3 | pages = 399–406 | date = March 2006 | pmid = 16544944 | pmc = 2570754 | doi = 10.1021/tx050283e }} free text and degradation of iron sulfur centers into iron ions and iron-nitrosyl compounds.{{cite journal | vauthors = Hibbs JB, Taintor RR, Vavrin Z, Rachlin EM | title = Nitric oxide: a cytotoxic activated macrophage effector molecule | journal = Biochemical and Biophysical Research Communications | volume = 157 | issue = 1 | pages = 87–94 | date = November 1988 | pmid = 3196352 | doi = 10.1016/S0006-291X(88)80015-9 }}

Two important biological reaction mechanisms of NO are S-nitrosation of thiols, and nitrosylation of transition metal ions. S-nitrosation involves the (reversible) conversion of thiol groups, including cysteine residues in proteins, to form S-nitrosothiols (RSNOs). S-Nitrosation is a mechanism for dynamic, post-translational regulation of most or all major classes of protein.{{cite book | veditors = van Faassen E, Vanin A |title= Radicals for life: the various forms of nitric oxide |date=2007 |publisher=Elsevier |location=Amsterdam |isbn=978-0-444-52236-8}} 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. 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.{{cite book | veditors = van Faassen E, Vanin A |title=Encyclopedia of analytical science |date=2005 |publisher=Elsevier |location=[Amsterdam] |isbn=978-0-12-764100-3 |edition=2nd}}

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 and aconitase, activation of the soluble guanylate cyclase, ADP ribosylation of proteins, protein sulfhydryl group nitrosylation, and iron regulatory factor activation.{{cite journal | vauthors = Shami PJ, Moore JO, Gockerman JP, Hathorn JW, Misukonis MA, Weinberg JB | title = Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukemia cells | journal = Leukemia Research | volume = 19 | issue = 8 | pages = 527–533 | date = August 1995 | pmid = 7658698 | doi = 10.1016/0145-2126(95)00013-E }} NO has been demonstrated to activate NF-κB in peripheral blood mononuclear cells, an important transcription factor in iNOS gene expression in response to inflammation.{{cite journal | vauthors = Kaibori M, Sakitani K, Oda M, Kamiyama Y, Masu Y, Nishizawa M, Ito S, Okumura T | title = Immunosuppressant FK506 inhibits inducible nitric oxide synthase gene expression at a step of NF-kappaB activation in rat hepatocytes | journal = Journal of Hepatology | volume = 30 | issue = 6 | pages = 1138–1145 | date = June 1999 | pmid = 10406194 | doi = 10.1016/S0168-8278(99)80270-0 }}

{{Further|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.{{cite journal | vauthors = Wu L, Wang R | title = Carbon monoxide: endogenous production, physiological functions, and pharmacological applications | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 585–630 | date = December 2005 | pmid = 16382109 | doi = 10.1124/pr.57.4.3 | s2cid = 17538129 }}{{cite journal | vauthors = Olas B | title = Carbon monoxide is not always a poison gas for human organism: Physiological and pharmacological features of CO | journal = Chemico-Biological Interactions | volume = 222 | issue = 5 October 2014 | pages = 37–43 | date = October 2014 | pmid = 25168849 | doi = 10.1016/j.cbi.2014.08.005 | bibcode = 2014CBI...222...37O }}{{cite journal | vauthors = Li L, Hsu A, Moore PK | title = Actions and interactions of nitric oxide, carbon monoxide and hydrogen sulphide in the cardiovascular system and in inflammation--a tale of three gases! | journal = Pharmacology & Therapeutics | volume = 123 | issue = 3 | pages = 386–400 | date = September 2009 | pmid = 19486912 | doi = 10.1016/j.pharmthera.2009.05.005 | doi-access = free }} Mammals maintain a baseline 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 (HMOX) which has been estimated to account for 86% of endogenous CO production. Other contributing sources include: the microbiome, cytochrome P450 reductase, human acireductone dioxygenase, tyrosinase, lipid peroxidation, alpha-keto acids, 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.{{cite journal | vauthors = Hopper CP, De La Cruz LK, Lyles KV, Wareham LK, Gilbert JA, Eichenbaum Z, Magierowski M, Poole RK, Wollborn J, Wang B | title = Role of Carbon Monoxide in Host-Gut Microbiome Communication | journal = Chemical Reviews | volume = 120 | issue = 24 | pages = 13273–13311 | date = December 2020 | pmid = 33089988 | doi = 10.1021/acs.chemrev.0c00586 | s2cid = 224824871 }}

The biomedical study of CO traces back to factitious airs in the 1790s when Thomas Beddoes, James Watt, James Lind, and many others investigated beneficial effects of hydrocarbonate (water gas) inhalation.{{cite journal | vauthors = Hopper CP, Zambrana PN, Goebel U, Wollborn J | title = A brief history of carbon monoxide and its therapeutic origins | journal = Nitric Oxide | volume = 111-112 | pages = 45–63 | date = June 2021 | pmid = 33838343 | doi = 10.1016/j.niox.2021.04.001 | s2cid = 233205099 }} Following Solomon Snyder's first report that CO is a normal neurotransmitter in 1993,{{cite journal | vauthors = Verma A, Hirsch DJ, Glatt CE, Ronnett GV, Snyder SH | title = Carbon monoxide: a putative neural messenger | journal = Science | volume = 259 | issue = 5093 | pages = 381–384 | date = January 1993 | pmid = 7678352 | doi = 10.1126/science.7678352 | bibcode = 1993Sci...259..381V }}{{cite news| vauthors = Kolata G |date=January 26, 1993|title=Carbon Monoxide Gas Is Used by Brain Cells As a Neurotransmitter|newspaper=The New York Times|url=https://www.nytimes.com/1993/01/26/science/carbon-monoxide-gas-is-used-by-brain-cells-as-a-neurotransmitter.html?pagewanted=1|access-date=May 2, 2010}} CO has received significant clinical attention as a biological regulator. Unlike NO and {{chem|H|2|S}}, CO is an inert molecule with remarkable chemical stability capable of diffusing through membranes to exert its effects locally and in distant tissues.{{cite journal | vauthors = Yang X, Lu W, Wang M, Tan C, Wang B | title = "CO in a pill": Towards oral delivery of carbon monoxide for therapeutic applications | journal = Journal of Controlled Release | volume = 338 | pages = 593–609 | date = September 2021 | pmid = 34481027 | doi = 10.1016/j.jconrel.2021.08.059 | pmc = 8526413 }} CO has been shown to interact with molecular targets including soluble guanylyl cyclase, mitochondrial oxidases, catalase, nitric oxide synthase, mitogen-activated protein kinase, PPAR gamma, HIF1A, NRF2, ion channels, cystathionine beta synthase, and numerous other functionalities.{{cite journal | vauthors = Yang X, de Caestecker M, Otterbein LE, Wang B | title = Carbon monoxide: An emerging therapy for acute kidney injury | journal = Medicinal Research Reviews | volume = 40 | issue = 4 | pages = 1147–1177 | date = July 2020 | pmid = 31820474 | pmc = 7280078 | doi = 10.1002/med.21650 }} It is widely accepted that CO primarily exerts its effects in mammals primarily through interacting with ferrous ion complexes such as the prosthetic heme moiety of hemoproteins. 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.

{{Main|Biological functions of hydrogen sulfide}}

Hydrogen sulfide ({{chem|H|2|S}}) has important signaling functions in mammalian physiology.{{cite journal | vauthors = Paul BD, Snyder SH | title = Gasotransmitter hydrogen sulfide signaling in neuronal health and disease | journal = Biochemical Pharmacology | volume = 149 | pages = 101–109 | date = March 2018 | pmid = 29203369 | pmc = 5868969 | doi = 10.1016/j.bcp.2017.11.019 }} The gas is produced enzymatically by cystathionine beta-synthase and cystathionine gamma-lyase, endogenous non-enzymatic reactions,{{cite journal | vauthors = Feng Y, Prokosch V, Liu H | title = Current Perspective of Hydrogen Sulfide as a Novel Gaseous Modulator of Oxidative Stress in Glaucoma | journal = Antioxidants | volume = 10 | issue = 5 | pages = 671 | date = April 2021 | pmid = 33925849 | doi = 10.3390/antiox10050671 | pmc = 8146617 | doi-access = free }} and may also be produced by the microbiome.{{cite journal | vauthors = Tomasova L, Konopelski P, Ufnal M | title = Gut Bacteria and Hydrogen Sulfide: The New Old Players in Circulatory System Homeostasis | journal = Molecules | volume = 21 | issue = 11 | pages = 1558 | date = November 2016 | pmid = 27869680 | pmc = 6273628 | doi = 10.3390/molecules21111558 | doi-access = free }} Eventually the gas is converted to sulfite in the mitochondria by thiosulfate reductase, and the sulfite is further oxidized to thiosulfate and sulfate by sulfite oxidase. The sulfates are excreted in the urine.{{cite journal | vauthors = Kamoun P | title = [H2S, a new neuromodulator] | journal = Médecine/Sciences | volume = 20 | issue = 6–7 | pages = 697–700 | date = July 2004 | pmid = 15329822 | doi = 10.1051/medsci/2004206-7697 | doi-access = free }}

{{chem|H|2|S}} acts as a relaxant of smooth muscle and as a vasodilator.{{cite journal | vauthors = Lefer DJ | title = A new gaseous signaling molecule emerges: cardioprotective role of hydrogen sulfide | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 46 | pages = 17907–17908 | date = November 2007 | pmid = 17991773 | pmc = 2084269 | doi = 10.1073/pnas.0709010104 | bibcode = 2007PNAS..10417907L | doi-access = free }} Though both NO and {{chem|H|2|S}} have been shown to relax blood vessels, their mechanisms of action are different: while NO activates the enzyme guanylyl cyclase, {{chem|H|2|S}} activates ATP-sensitive potassium channels in smooth muscle cells. Researchers are not clear how the vessel-relaxing responsibilities are shared between NO and {{chem|H|2|S}}. However, there exists some evidence to suggest that NO does most of the vessel-relaxing work in large vessels and {{chem|H|2|S}} is responsible for similar action in smaller blood vessels.{{cite journal | vauthors = Wang R | title = Toxic gas, lifesaver | journal = Scientific American | volume = 302 | issue = 3 | pages = 66–71 | date = March 2010 | pmid = 20184185 | doi = 10.1038/scientificamerican0310-66 | bibcode = 2010SciAm.302c..66W }} {{chem|H|2|S}} deficiency can be detrimental to the vascular function after an acute myocardial infarction (AMI). {{chem|H|2|S}} therapy reduces myocardial injury and reperfusion complications.{{cite journal | vauthors = King AL, Polhemus DJ, Bhushan S, Otsuka H, Kondo K, Nicholson CK, Bradley JM, Islam KN, Calvert JW, Tao YX, Dugas TR, Kelley EE, Elrod JW, Huang PL, Wang R, Lefer DJ | title = Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 8 | pages = 3182–3187 | date = February 2014 | pmid = 24516168 | pmc = 3939925 | doi = 10.1073/pnas.1321871111 | bibcode = 2014PNAS..111.3182K | doi-access = free }}{{cite journal | vauthors = Powell CR, Dillon KM, Matson JB | title = A review of hydrogen sulfide (H₂S) donors: Chemistry and potential therapeutic applications | journal = Biochemical Pharmacology | volume = 149 | pages = 110–123 | date = March 2018 | pmid = 29175421 | pmc = 5866188 | doi = 10.1016/j.bcp.2017.11.014 }} Due to its effects similar to NO (without its potential to form peroxides by interacting with superoxide), {{chem|H|2|S}} is now recognized as potentially protecting against cardiovascular disease.{{cite journal | vauthors = Benavides GA, Squadrito GL, Mills RW, Patel HD, Isbell TS, Patel RP, Darley-Usmar VM, Doeller JE, Kraus DW | title = Hydrogen sulfide mediates the vasoactivity of garlic | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 46 | pages = 17977–17982 | date = November 2007 | pmid = 17951430 | pmc = 2084282 | doi = 10.1073/pnas.0705710104 | bibcode = 2007PNAS..10417977B | doi-access = free | author7-link = Victor Darley-Usmar }}

Recent findings suggest strong cellular crosstalk of NO and {{chem|H|2|S}},{{cite journal | vauthors = Coletta C, Papapetropoulos A, Erdelyi K, Olah G, Módis K, Panopoulos P, Asimakopoulou A, Gerö D, Sharina I, Martin E, Szabo C | title = Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 23 | pages = 9161–9166 | date = June 2012 | pmid = 22570497 | pmc = 3384190 | doi = 10.1073/pnas.1202916109 | bibcode = 2012PNAS..109.9161C | doi-access = free }} demonstrating that the vasodilatatory effects of these two gases are mutually dependent. Additionally, {{chem|H|2|S}} reacts with intracellular S-nitrosothiols to form the smallest S-nitrosothiol (HSNO), and a role of {{chem|H|2|S}} in controlling the intracellular S-nitrosothiol pool has been suggested.{{cite journal | vauthors = Filipovic MR, Miljkovic JL, Nauser T, Royzen M, Klos K, Shubina T, Koppenol WH, Lippard SJ, Ivanović-Burmazović I | title = Chemical characterization of the smallest S-nitrosothiol, HSNO; cellular cross-talk of H2S and S-nitrosothiols | journal = Journal of the American Chemical Society | volume = 134 | issue = 29 | pages = 12016–12027 | date = July 2012 | pmid = 22741609 | pmc = 3408084 | doi = 10.1021/ja3009693 }}

Some gaseous signaling molecules may be a gasotransmitter, notably methane and cyanide.{{cite journal | vauthors = Boros M, Tuboly E, Mészáros A, Amann A | title = The role of methane in mammalian physiology-is it a gasotransmitter? | journal = Journal of Breath Research | volume = 9 | issue = 1 | pages = 014001 | date = January 2015 | pmid = 25624411 | doi = 10.1088/1752-7155/9/1/014001 | s2cid = 12167059 | bibcode = 2015JBR.....9a4001B | url = https://publicatio.bibl.u-szeged.hu/11753/1/Boros_J_Breath_Res_2015_u.pdf }}{{cite journal | vauthors = Pacher P | title = Cyanide emerges as an endogenous mammalian gasotransmitter | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 118 | issue = 25 | pages = e2108040118 | date = June 2021 | pmid = 34099579 | pmc = 8237670 | doi = 10.1073/pnas.2108040118 | doi-access = free | bibcode = 2021PNAS..11808040P }} 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 as an essential gasotransmitter, similar to that of essential amino acids.{{cite journal | vauthors = Wareham LK, Southam HM, Poole RK | title = Do nitric oxide, carbon monoxide and hydrogen sulfide really qualify as 'gasotransmitters' in bacteria? | journal = Biochemical Society Transactions | volume = 46 | issue = 5 | pages = 1107–1118 | date = October 2018 | pmid = 30190328 | pmc = 6195638 | doi = 10.1042/BST20170311 | doi-access = free }}

{{reflist}}

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

{{Neurotransmitters}}

Category:Neurotransmitters

Category:Gaseous signaling molecules