Gas biology: small molecular medicine

Abstract

In this special issue of the Journal of Molecular Medicine, we present five review articles concerning small molecules that play big roles in physiology and medicine: the gases oxygen (O 2 ), nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S). Of these, the essential requirement for O 2 is well known to physicians, scientists, and laymen alike. However, it is only within the last two decades that we have begun to understand the molecular mechanisms by which every cell in our body senses the local O 2 concentration and responds to reduced O 2 availability (i.e., hypoxia) with changes in gene expression that are mediated by the hypoxia-inducible factors HIF-1 and HIF-2 [1]. Recent evidence suggest that NO, CO, and H 2 S function as signaling molecules that also play critical roles in regulating O 2 homeostasis.Philip Marsden and colleagues (University of Toronto) describe the fascinating crosstalk between O 2 sensing and NO signaling that occurs to regulate red blood cell levels and blood vessel tone, which together play critical roles in O 2 delivery [2]. In particular, they discuss exciting data from their lab demonstrating that the physiological responses to anemic hypoxia (reduced O 2 carrying capacity) and hypoxic hypoxia (reduced O 2 ) are mechanistically distinct. This difference is dramatically illustrated by their finding that subjecting mice that lack neuronal NO synthase (also known as nNOS or NOS1) to anemic hypoxia resulted in an increased mortality rate, compared to wild-type mice, whereas these NOS1-deficient mice were protected against mortality during hypoxic hypoxia [3]. Their delineation of the molecular and cellular basis for these effects is truly elegant physiology. The crosstalk between O 2 sensing and NO signaling is extensive and includes increased expression of inducible NOS (also known as iNOS or NOS2) under hypoxic conditions that is mediated by HIF-1 [4,5] and the regulation of HIF-1 activity by S-nitrosylation of a cysteine residue in the HIF-1α subunit [6].Puneet Anand and Jonathan Stamler (Case Western Reserve University) provide a global view of protein Snitrosylation and its effects on protein function [7]. They describe several different molecular mechanisms by which proteins are nitrosylated and counteracting mechanisms by which they are denitrosylated, which is analogous to the phosphorylation and dephosphorylation of proteins by kinases and phosphatases. The balance between nitrosylation and denitrosylation is dependent on the redox state of the cell, thus establishing inherent crosstalk between NO and reactive oxygen species. The authors discuss several examples of diseases associated with dysregulated S-nitrosylation, which may therefore represent a novel therapeutic target.Makoto Suetmatsu and colleagues (Keio University) discuss the biological role of CO, which is generated by heme oxygenases (HO1 and HO2) using heme and O 2 as

Gasotransmitters, poisons, and antimicrobials: it's a gas, gas, gas!

“…Most recently, H 2 S has emerged as a third gasotransmitter, with key roles in the nervous and cardiovascular systems and regulation of cellular and whole body metabolism (reviewed in [14,15]). The literature on the biology of these three gases is now so vast that these and other reviews must act as a surrogate for the relevant papers: [16-20]. In the microbial world too, all three gases have important long-recognised roles: NO is an intermediate in denitrification [21] and is detoxified by pathogens [22,23], CO is an unusual carbon and energy source [24], and H 2 S is well known to all microbiologists as a product of anoxic sulfate respiration [25].…”

Interaction of Hydrogen Sulfide with Oxygen Sensing under Hypoxia

“…With the remarkable sensitivity and the fast speed to hypoxic response, the carotid body plays a unique role in O 2 sensing [ 19 ]. Carotid bodies are small sensory organs located at the bifurcation of the common carotid artery [ 14 , 19 ]. Changes in O 2 levels of arterial blood rapidly active the carotid bodies, which in turn transduce sensory information to brainstem neurons [ 14 ].…”

“…Carotid bodies are small sensory organs located at the bifurcation of the common carotid artery [ 14 , 19 ]. Changes in O 2 levels of arterial blood rapidly active the carotid bodies, which in turn transduce sensory information to brainstem neurons [ 14 ]. The final response in the central nervous system regulates vital functions including breathing, heart rate, and blood pressure to increase ventilation and systemic delivery of oxygen [ 15 ].…”

“…Endogenous H 2 S levels have been reported in different mammalian systems, ranging from 50 to 160 μ M [ 6 , 7 ]. The enzymatic production of endogenous H 2 S were identified, mostly composed of cystathionine β -synthase (CBS) [ 8 – 10 ], cystathionine γ -lyase (CSE) [ 11 – 13 ], and 3-mercaptopyruvate sulfurtransferase (MST) [ 14 – 16 ].…”

TRP channels: sensors and transducers of gasotransmitter signals

“…Secondly, they exert their biological actions via a variety of interactions with macromolecules: covalent binding of gases to prosthetic metal complexes in receptor proteins; non-covalent binding to the regulatory subunits of proteins; and space occupancy in and around the protein structure that impedes the access of other gases to the functionally critical protein motifs. Recent evidence suggest that NO, CO, H 2 S, and CO 2 function as signaling molecules that also play critical roles in mediating the biological effects of changes in O 2 availability (Semenza and Prabhakar, 2012). …”