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Gasotransmitter

May 07, 2024

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

The name gasotransmitter is not intended to suggest a gaseous physical state such as infinitesimally small gas bubbles; the physical state is dissolution in complex body fluids and 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 edit

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;
  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.

Overview edit

The current "trinity" of 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 beneficial effects of these endogenous molecules have inspired significant pharmaceutical drug development efforts for each gas.

The triad of gases have many similar features and participate in shared signaling pathways, although their actions can either be synergistic or as an antagonistic regulator.[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 phylogenetic kingdoms, however, exemplified by the important interactions of carbon monoxide with nickel or molybdenum carbon monoxide dehydrogenase enzymes.[8][9]

Gasotransmitters are under investigation in disciplines such as: 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 kingdoms.[22][23][24][25]

Many analytical tools have been developed to assist in the study of gasotransmitters.[26]

Nitric oxide edit

Main article: 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.[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 (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.[29][30] 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.[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.[34]

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.[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, diabetes, or 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, 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, macrophages, and neutrophils) as part of the human immune response.[38] 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.[39][40][41] 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.[42] NO is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites, including Leishmania[43] and 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 compounds.[50]

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.[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. 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 and aconitase, activation of the soluble guanylate cyclase, ADP ribosylation of proteins, protein sulfhydryl group nitrosylation, and iron regulatory factor activation.[53] 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.[54]

NO can be problematic under certain circumstances if it reacts with superoxide to produce the damaging oxidant peroxynitrite.

Pharmaceutical initiatives include: Nitroglycerin and amyl nitrite serve as vasodilators because they are converted to nitric oxide in the body. The vasodilating antihypertensive drug minoxidil contains an NO moiety and may act as an NO agonist. The mechanism of action for sildenafil (Viagra) is closely related to NO signaling. Inhaled NO may improve survival and recovery from paraquat poisoning.

Carbon monoxide edit

Further information: 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.[55][56][57] 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.[8]

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.[58] Following Solomon Snyder's 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, mitochondrial oxidases, catalase, nitric oxide synthase, mitogen-activated protein kinase, PPAR gamma, HIF1A, NRF2, ion channels, 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 complexes such as the prosthetic heme moiety of hemoproteins.[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]

Studies involving carbon monoxide have been conducted in many laboratories throughout the world for its anti-inflammatory and cytoprotective properties.[19] These properties have potential to be used to prevent the development of a series of pathological conditions including ischemia reperfusion injury, transplant rejection, atherosclerosis, severe sepsis, severe malaria, autoimmunity, and many other indications.[63][64]

Hydrogen sulfide edit

Main article: Biological functions of hydrogen sulfide

Hydrogen sulfide (H
2S) has important signaling functions in mammalian physiology.[65] The gas is produced enzymatically by cystathionine beta-synthase and cystathionine gamma-lyase, endogenous non-enzymatic reactions,[66] and may also be produced by the microbiome.[67] 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.[68]

H
2S acts as a relaxant of smooth muscle and as a vasodilator.[69] 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, H
2S activates ATP-sensitive potassium channels 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.[70] H
2S deficiency can be detrimental to the vascular function after an acute myocardial infarction (AMI). H
2S therapy reduces myocardial injury and reperfusion complications.[71][72] Due to its effects similar to NO (without its potential to form peroxides by interacting with superoxide), H
2S is now recognized as potentially protecting against cardiovascular disease.[69][73]

Recent findings suggest strong cellular crosstalk of NO and H
2S,[74] demonstrating that the vasodilatatory effects of these two gases are mutually dependent. Additionally, H
2S reacts with intracellular S-nitrosothiols to form the smallest S-nitrosothiol (HSNO), and a role of H
2S in controlling the intracellular S-nitrosothiol pool has been suggested.[75]

H
2S is also active in the brain, where it increases the response of the NMDA receptor and facilitates long term potentiation,[76] which is involved in the formation of memory. In Alzheimer's disease and Parkinson's disease the brain's H
2S concentration is severely decreased.[77][78]

The beneficial effects of H
2S signaling inspired pharmaceutical development initiatives.[79] Akin to NO, presenting possible new therapy opportunities for erectile dysfunction.[80] In 2005, it was shown that mice can be put into a state of suspended animation-like hypothermia by applying a low dosage of H
2S.[81][82]

Excess endogenous production of H
2S can be problematic in disorders such as trisomy 21 (Down syndrome)[68] and type 1 diabetes.[70]

Gasotransmitter candidates edit

Some gaseous signaling molecules may be a gasotransmitter, notably methane and cyanide.[83][84] 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.[85]

External links edit

  • European Network on Gasotransmitters (ENOG)

References edit

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May 07, 2024
gasotransmitter, class, neurotransmitters, molecules, distinguished, from, other, bioactive, endogenous, gaseous, signaling, molecules, based, need, meet, distinct, characterization, criteria, currently, only, nitric, oxide, carbon, monoxide, hydrogen, sulfide. Gasotransmitters is a class of neurotransmitters The molecules are distinguished from other bioactive endogenous gaseous signaling molecules based on a need to meet distinct characterization criteria Currently only nitric oxide carbon monoxide and hydrogen sulfide are accepted as gasotransmitters 1 According to in vitro models gasotransmitters like other gaseous signaling molecules may bind to gasoreceptors and trigger signaling in the cells 1 The name gasotransmitter is not intended to suggest a gaseous physical state such as infinitesimally small gas bubbles the physical state is dissolution in complex body fluids and 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 Contents 1 Criteria 2 Overview 3 Nitric oxide 4 Carbon monoxide 5 Hydrogen sulfide 6 Gasotransmitter candidates 7 External links 8 ReferencesCriteria editThe 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 It is a small molecule of gas 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 It is endogenously and enzymatically generated and its production is regulated It has well defined and specific functions at physiologically relevant concentrations Thus manipulating the endogenous levels of this gas evokes specific physiological changes Functions of this endogenous gas can be mimicked by its exogenously applied counterpart Its cellular effects may or may not be mediated by second messengers but should have specific cellular and molecular targets Overview editThe current trinity of 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 beneficial effects of these endogenous molecules have inspired significant pharmaceutical drug development efforts for each gas The triad of gases have many similar features and participate in shared signaling pathways although their actions can either be synergistic or as an antagonistic regulator 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 phylogenetic kingdoms however exemplified by the important interactions of carbon monoxide with nickel or molybdenum carbon monoxide dehydrogenase enzymes 8 9 Gasotransmitters are under investigation in disciplines such as 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 kingdoms 22 23 24 25 Many analytical tools have been developed to assist in the study of gasotransmitters 26 Nitric oxide editMain article 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 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 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 29 30 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 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 34 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 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 diabetes or 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 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 macrophages and neutrophils as part of the human immune response 38 Phagocytes are armed with inducible nitric oxide synthase iNOS which is activated by interferon gamma IFN g as a single signal or by tumor necrosis factor TNF along with a second signal 39 40 41 On the other hand transforming growth factor beta TGF b 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 42 NO is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites including Leishmania 43 and 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 compounds 50 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 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 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 and aconitase activation of the soluble guanylate cyclase ADP ribosylation of proteins protein sulfhydryl group nitrosylation and iron regulatory factor activation 53 NO has been demonstrated to activate NF kB in peripheral blood mononuclear cells an important transcription factor in iNOS gene expression in response to inflammation 54 NO can be problematic under certain circumstances if it reacts with superoxide to produce the damaging oxidant peroxynitrite Pharmaceutical initiatives include Nitroglycerin and amyl nitrite serve as vasodilators because they are converted to nitric oxide in the body The vasodilating antihypertensive drug minoxidil contains an NO moiety and may act as an NO agonist The mechanism of action for sildenafil Viagra is closely related to NO signaling Inhaled NO may improve survival and recovery from paraquat poisoning Carbon monoxide editFurther information 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 55 56 57 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 8 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 58 Following Solomon Snyder s 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 H2 S 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 mitochondrial oxidases catalase nitric oxide synthase mitogen activated protein kinase PPAR gamma HIF1A NRF2 ion channels 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 complexes such as the prosthetic heme moiety of hemoproteins 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 Studies involving carbon monoxide have been conducted in many laboratories throughout the world for its anti inflammatory and cytoprotective properties 19 These properties have potential to be used to prevent the development of a series of pathological conditions including ischemia reperfusion injury transplant rejection atherosclerosis severe sepsis severe malaria autoimmunity and many other indications 63 64 Hydrogen sulfide editMain article Biological functions of hydrogen sulfide Hydrogen sulfide H2 S has important signaling functions in mammalian physiology 65 The gas is produced enzymatically by cystathionine beta synthase and cystathionine gamma lyase endogenous non enzymatic reactions 66 and may also be produced by the microbiome 67 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 68 H2 S acts as a relaxant of smooth muscle and as a vasodilator 69 Though both NO and H2 S have been shown to relax blood vessels their mechanisms of action are different while NO activates the enzyme guanylyl cyclase H2 S activates ATP sensitive potassium channels in smooth muscle cells Researchers are not clear how the vessel relaxing responsibilities are shared between NO and H2 S However there exists some evidence to suggest that NO does most of the vessel relaxing work in large vessels and H2 S is responsible for similar action in smaller blood vessels 70 H2 S deficiency can be detrimental to the vascular function after an acute myocardial infarction AMI H2 S therapy reduces myocardial injury and reperfusion complications 71 72 Due to its effects similar to NO without its potential to form peroxides by interacting with superoxide H2 S is now recognized as potentially protecting against cardiovascular disease 69 73 Recent findings suggest strong cellular crosstalk of NO and H2 S 74 demonstrating that the vasodilatatory effects of these two gases are mutually dependent Additionally H2 S reacts with intracellular S nitrosothiols to form the smallest S nitrosothiol HSNO and a role of H2 S in controlling the intracellular S nitrosothiol pool has been suggested 75 H2 S is also active in the brain where it increases the response of the NMDA receptor and facilitates long term potentiation 76 which is involved in the formation of memory In Alzheimer s disease and Parkinson s disease the brain s H2 S concentration is severely decreased 77 78 The beneficial effects of H2 S signaling inspired pharmaceutical development initiatives 79 Akin to NO presenting possible new therapy opportunities for erectile dysfunction 80 In 2005 it was shown that mice can be put into a state of suspended animation like hypothermia by applying a low dosage of H2 S 81 82 Excess endogenous production of H2 S can be problematic in disorders such as trisomy 21 Down syndrome 68 and type 1 diabetes 70 Gasotransmitter candidates editSome gaseous signaling molecules may be a gasotransmitter notably methane and cyanide 83 84 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 85 External links editEuropean Network on Gasotransmitters ENOG References edit a b Mustafa AK Gadalla MM Snyder SH April 2009 Signaling by gasotransmitters Science Signaling 2 68 re2 doi 10 1126 scisignal 268re2 PMC 2744355 PMID 19401594 Simpson PV Schatzschneider U 2014 04 18 Release of Bioactive Molecules Using Metal Complexes In Gasser G ed Inorganic Chemical Biology Chichester UK John Wiley amp Sons Ltd pp 309 339 doi 10 1002 9781118682975 ch10 ISBN 978 1 118 68297 5 a b Wang R November 2002 Two s company three s a crowd can H2S be the 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