Gasotransmitter
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
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]
- 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
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:
Many analytical tools have been developed to assist in the study of gasotransmitters.[26]
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.
It is a known bioproduct in almost all types of organisms, ranging from bacteria to plants, fungi, and animal cells.
The production of NO is elevated in populations living at high altitudes, which helps these people avoid
NO is also generated by phagocytes (
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:
Carbon monoxide
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
The biomedical study of CO traces back to
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
Hydrogen sulfide (H
2S) has important signaling functions in mammalian physiology.
H
2S acts as a relaxant of
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
2S concentration is severely decreased.[77][78]
The beneficial effects of H
2S signaling inspired pharmaceutical development initiatives.
2S.[81][82]
Excess endogenous production of H
2S can be problematic in disorders such as
Gasotransmitter candidates
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
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