Gasotransmitters

Rui Wang, Rui Wang

• Editore: Royal Society of Chemistry
• Anno: 2018
• ISBN:
  9781788014809
• Edizione: 1
• Argomento: Sciences physiques
• Categoria: Chimie

Gasotransmitters are gas molecules produced endogenously in prokaryotic and eukaryotic cells for signalling purposes. This book provides, for the first time, a comprehensive description and systematic look at all gasotransmitters, established or proposed, since their detection in 2002. The content and scope covers the production, metabolism, and signalling roles of gasotransmitters. Conceptual advances, scientific discoveries and newly developed techniques described in this book influence our understanding of fundamental molecular and cellular events in biology and medicine.

This book serves as the state-of-the-art book for undergraduate and graduate students as well as post-doctoral fellows in biomedical disciplines and toxicologists studying the toxic mechanisms of gasotransmitters in the environment. It will also be welcomed by researchers in university and research institutes, government agencies, pharmaceutical and medical instrument industry, and clinical practice.

Chapter 1

Overview of Gasotransmitters and the Related Signaling Network

Rui Wang

Department of Biology, Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Ontario, Canada P3E2C6

Email: [email protected]

A system cannot be or remain a system without well-oiled and coordinated actions of all of its components or building parts which interact with each other to receive, deliver, integrate, and differentiate information via vast and intertwined networks. Using ‘information’ as signals and ‘information webs’ as signaling networks, all systems, as large as the world and as small as an intracellular organelle, function in the same fashion, from the distant past to the immediate present, and this will not change in the indefinite future.

Setting up flares to send out smoke signals in Ancient China alerted of an enemy invasion. A second beacon tower, upon seeing from a distance the smoke from the first beacon tower would light up a fire and send out its own smoke signal. This consequential smoke relay transmitted the signal of imminent danger over hundreds of kilometers within hours. Eventually, the visual signals would be transformed into army movement and a battle. In ancient Greek legends, a vocal signal was delivered over 35–40 km in over 3–4 h before the messenger collapsed. This messenger who ran from Marathon to Athens to report the victory of the Battle of Marathon is one of the most famous ‘signal’ carriers in human history. In the 21st century, our societies are bombarded by a large amount of signals and we have become accustomed to the velocity, versatility, and complexity of state-of-the-art signaling networks thanks to the internet, Twitter, Facebook, Instagram, and WeChat. The role of signals and signal networks in our modern society has become more important than ever.

You know by now what I am going to state next, and you are right. Gasotransmitters and their networks are the Twitter, Facebook, Instagram, and WeChat of life, human bodies, systems and organs, mammalian cells and intracellular organelles, bacteria and virus, or plants. The elucidation and description of the molecular and structural features of gasotransmitters, their production pathways, signaling mechanisms, cellular and molecular targets, and functional impact in prokaryotic and eukaryotic cells are the focus of this book. This chapter aims to provide an overview on the conceptualization of gasotransmitters as well as their interactions.

1.1 Conceptualization and Evaluation Systems for Gasotransmitters

Conceptual advances, scientific discoveries, and newly developed techniques impact our understanding of fundamental molecular and cellular events in biology and medicine. I proposed the establishment of the ‘gasotransmitter’ concept and framework firstly in 2002 to characterize and clarify a class of endogenous gas molecules, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S), that function as signaling molecules to direct various molecular and cellular events.¹ Over the last 15 years, this concept has continuously evolved and been refined² with recent updates.³ The birth of the gasotransmitter framework deepened our understanding of cellular signaling processes, leading to the discovery of new pathogenic mechanisms and therapeutic strategies for related diseases. New gasotransmitters have been identified or suggested, such as NH₃.

Similar to the bacterial origin of H₂S in mammalian systems, methanogenesis in mammals is traditionally solely attributed to anaerobic microbial activity in the gastrointestinal tract. Studies in recent years have suggested that non-microbial methane formation may be a biologically relevant process in plants and animals.⁴ Evidence has also been provided that endogenously generated methane may play a number of roles in the regulation of various and selective physiological functions. Interestingly, methanogenesis in mammals appears to be upregulated by hypoxia, suggesting the importance of this gas molecule for mammalian cells in dealing with the transition and adaptation to aerobic and anaerobic environments. Insufficient evidence, on the other hand, exists to support a full qualification of methane as a gasotransmitter against the six gasotransmitter criteria. However, the involvement of endogenous methane in redox regulation and mitochondrial function invites more intensive and in-depth research into methane-related physiological and biological events.

From the research capacity building point of view, the gasotransmitter concept has become a proliferative catalyst. Many programs or organizations on gasotransmitters have been created. The European Network on Gasotransmitters was created in 2011. The gasotransmitter concept has been included in the curriculum of many universities worldwide. A Google search of ‘gasotransmitter’ yields ∼31 300 results (Mar. 28, 2018). An incomplete data search found four books with the word ‘gasotransmitter’ in their titles (Signal Transduction and the gasotransmitters: NO, CO, and H₂S in Biology and Medicine, 2004; Gasotransmitter – Physiology and Pathophysiology, 2012; Gasotransmitters: novel regulators of ion channels and transporters, 2012; Gasotransmitters in Plants – The Rise of a New Paradigm in Cell Signaling, 2016).

The following set of criteria defines the character and roles of gasotransmitters.

1. Gasotransmitters are small molecules of gas. In sharp contrast to numerous endogenous substances, gasotransmitters exist in gaseous form or are dissolved in circulation, interstitial fluid, lymph, or intracellular fluid. This criterion is inclusive, rather than exclusive, to account for derivatives of primary gasotransmitters. Gasotransmitters must have a light molecular weight, but their derivatives can present a light or heavy molecular weight and may no longer be in gas state. Regardless, these derivatives are still part of the gasotransmitter family. The derivatives of NO, such as nitrite (NO²⁻), nitrate (NO³⁻), nitrous oxide (N₂O), and nitroxyl (HNO), are examples of this inclusive concept of gasotransmitters. Together with persulfide, polysulfides are noticeable derivatives of H₂S, playing important gasotransmitter functions for H₂S or as H₂S.⁵ These H₂S derivatives also help buffer fluctuations in the H₂S levels. Compared to endogenous H₂S levels, the endogenous levels of polysulfides in cells and tissues are much higher. This is somehow related to the fact that polysulfide store and/or release H₂S when needed.⁵
   Polysulfides can be formed in different ways. Enzymatically, 3-mercaptopyruvate sulfur transfurase (MST) decomposes mercaptopyruvate into pyruvate and sulfur. While pyruvate is rapidly released, sulfur remains bound to MST and accumulates as non-diffusible polysulfides.⁶ After reaction of these polysulfides with thiols or sulfide, diffusible polysulfides may be consequently generated. The biological significance of this pathway is not clear as it relies on the cell type-specific expression of MST, and the diffusion and membrane permeability processes of the produced polysulfide are not straightforward. l-Cysteine competitively inhibits this pathway but mercaptoethanol activates it. The biogenesis of polysulfides can also stem from sulfide oxidation. One example of this path is the methemoglobin-dependent H₂S oxidation, leading to the generation of thiosulfate and hydropolysulfides.⁷ Moreover, the interaction of H₂S with NO or nitrosothiols through HSNO or after decomposition of SSNO⁻ leads to the formation of polysulfides.⁸ It should be noted that our understanding of the biosynthetic pathways and functional impact, as well as the underlying molecular and chemical mechanisms of polysulfides is still very limited.
   Polysulfides can be reduced to sulfide in the presence of strong nucleophiles or enzymatically with the aid of the thioredoxin system or other enzymes. The endogenous conditions governing the bidirectional reactions between polysulfides and H₂S remain still unclear. The elucidation of the conditions and further insight into the kinetics of these reactions will help solve the puzzle of whether the stronger cellular signaling effect of polysulfide compared to that of H₂S at the same molar concentration is simply due to the fact that each polysulfide molecule contains multiple H₂S molecules and to the fast kinetics of the polysulfide reduction to H₂S. On the other hand, the polymerization of polysulfides affords cyclo-octasulfur (S₈), and homolytic cleavage of polysulfides leads to the formation of sulfur radicals.
   Sulfur dioxide (SO₂) is another derivative of H₂S and its biological effects have been reported.⁹ NADPH oxidase, glutathione-dependent thiosulfate reductase, and thiosulfate sulfur transferase catalyze the oxidation of H₂S to SO₂.^10–12 In aqueous solution, sulfites may be formed by reaction of sulfide with O₂ with formation of SO₂^•− and S₂O₄²⁻.¹³ Sulfur oxidation or sulfate reduction has been shown to generate SO₂ in certain prokaryotes. Calcium-stimulated production of SO₂ in porcine coronary arteries has been reported.¹⁴ Currently, the in vivo SO₂ level is estimated using the proxy sulfite level. The sulfite level in rat plasma has been reported to range 10–15 µM.⁹
2. Gasotransmitters are freely permeable to cellular membranes. As such, their intracellular and intercellular movements do not exclusively rely on cognate membrane receptors or other transportation machineries.
   Lipid bilayers are the structural skeleton of plasmalemma and the membrane of intracellular organelles. Other constituents of cellular membranes include phospholipids, cholesterol, glycolipids, and proteins. Depending on the type of cells and organs where the lipid bilaye...