4117
J Physiol 594.15 (2016) pp 4117–4118
EDITORIAL
Gaseous regulation of Ca2+ homeostasis; for better or worse? Mark L. Dallas School of Pharmacy, University of Reading, Reading, RG6 6UB, UK
The Journal of Physiology
Email: [email protected]
Carbon monoxide (CO) and hydrogen sulfide (H2 S) are two gases well recognised for their toxic properties. Less well appreciated are their physiological functions within biological systems. To this end there has been a recent revival of interest in these so-called gasotransmitters and this has led to a greater understanding of their role in both physiology and pathology. It has also been suggested that they may be used to treat complex diseases. The idea of using toxic gases to treat human diseases would have seemed far-fetched to those researchers that trail blazed experiments looking at their endogenous production and function in the 1890s and again in the 1950s (Haldane, 1895; Sjostrand, 1949). As part of Physiology 2015; a symposium drew together scientists looking at the effects of the gasotransmitters on calcium signalling. The physiological role(s) of H2 S are diverse and published research to date indicates a diverse array of effects in a range of cell types. Elies et al. (2016) report on the effects of H2 S on the voltage gated calcium channel subfamily Cav3 (T-type), responsible for an array of cellular processes and implicated in nociception. Using the hydrogen sulfide salt NaHS, they previously reported isoform specific inhibition of Cav3.2 channels (Elies et al. 2014). A clear demonstration of this isoform specificity was that mutation of the Cav3.2 redox and H2 S sensitive extracellular residue resulted in the loss of H2 S sensitivity, and introduction of this residue to the previously H2 S insensitive Cav3.1 produced a response to NaHS. There is debate about the chemical tools used in the H2 S field, with questions over physiological concentrations of H2 S and the microdomains of H2 S activity. The development of new donors offers targeted approaches; however, robust measurements of in vivo H2 S concentrations are still outstanding. The need to determine a range of physiological H2 S concentrations is of growing concern, given the wide
ranging and often conflicting reports being published in the gasotransmitter field. Elies et al. (2016) argue that NaHS mediated effects are through H2 S mediated redox modulation of the Cav3.2 channels and not via H2 S’s ability to chelate Zn2+ . However, manipulation of endogenous H2 S production (via cystathionine γ-lyase (CSE) and/or cystathionine β-synthetase (CBS)) would further their argument. In this instance it seems unlikely that physiological levels of H2 S (believed to be in the nanomolar range) will influence T-type channel activity in the process of nociception; however, more robust H2 S donors and manipulation of endogenous H2 S levels (e.g. transgenic animals) will provide a more definitive answer than is currently available. Furthermore, a clearer picture of the role that T-type channels play in regulating pain associated neurotransmission will clear up some of the ‘controversies’ to which Elies et al. allude. The underlying mechanisms by which CO benefits cellular physiology form an emerging research field and one that the Vieira group has contributed to (Oliveira et al. 2016). In this article Oliveira et al. describe the potential for CO to provide cytoprotection through modulation of cellular defence mechanisms. They point to mitochondria as key organelles in the ability of CO to confer anti-apoptotic properties. This may seem contradictory,
C O
given that previous studies have highlighted an increase in reactive oxygen species (ROS) under CO exposure. This reported increase in ROS is important for anti-inflammatory signalling and is also implicated in the cytotoxicity of CO. However, this is contrasted with the proposed antioxidant role that CO plays, which acts through reducing ROS production. Different molecular substrates are likely to underlie this dual action of CO; NADPH oxidases and cytochrome c oxidase have both been proposed. The level to which CO mediated ROS elevation is beneficial to cellular physiology is likely to be both cell and microenvironment specific. Here again Oliveira et al. bring in Ca2+ homeostasis which mediates mitochondrial function, through multiple cellular cascades (e.g. mitochondrial membrane permeabilisation). From a neuroscience perspective this opens up the potential for differential CO modulation of cellular metabolism (neurones vs. glia). Work from the Vieira group (Almeida et al. 2012) focused on astrocytes and demonstrated that CO prevents astrocyte apoptosis via stimulation of oxidative phosphorylation. However, the true extent of CO in astrocytes in situ remains to be determined. Cancer researchers are also looking to manipulate cell metabolic status with CO or haem oxgenase (HO) modulators; this could have implications for apopotosis of cancer cells or reducing
H
S
H
Ca2+
Figure 1. Schematic illustration of carbon monoxide and hydrogen sulfide effects on modulating calcium homeostasis highlighted in this edition of The Journal of Physiology Elies et al. (2016) highlight the influence of H2 S on T-type calcium channels, while Oliveira et al. (2016) point to effects of CO on the mitochondria to influence calcium.
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
DOI: 10.1113/JP272693
4118 the aggressive proliferative nature of cancer cells. While proposed cellular targets of CO are pertinent to cancer biology through their regulation of intracellular Ca2+ , a definitive approach to tackling cancer evades us. This may be in part due to a lack of understanding of CO biology and how to exploit it for therapeutic effect, or the numerous cancer types and their diverse pathology. A cautionary tale for those interested in CO biology is oxygen (O2 ) availability and the model systems that have illustrated a host of CO effects. It is known that hypoxia, or lack of O2 , induces the haem oxygenase 1 enzyme, thus stimulating haem breakdown to produce CO. In addition, O2 and CO compete for the same molecular targets (via haem binding motifs); this is also the case for nitric oxide. Therefore current in vitro approaches limit our physiological understandings of CO at a systems level; it is this that needs to be addressed to unravel the predominant role for CO in cellular metabolism. In an exciting and rapidly evolving field it remains to be seen if CO and H2 S will develop into therapeutics of the future.
Editorial At a physiological level there is still much to be learnt about these gases and their impact on cellular physiology. It does, however, seem clear that Ca2+ homeostasis underpins an array of both H2 S and CO cellular actions, as illustrated by Elies et al (2016) and Oliveira et al (2016) (Fig. 1). However, with current clinical trials looking at the effects of inhaled CO on cardiovascular disease (https:// clinicaltrials.gov/ct2/show/NCT01523548), the gasotransmitters may be used therapeutically sooner than once thought.
J Physiol 594.15
Elies J, Scragg JL, Huang S, Dallas ML, Huang D, MacDougall D, Boyle JP, Gamper N & Peers C (2014). Hydrogen sulfide inhibits Cav3.2 T-type Ca2+ channels. FASEB J 28, 5376–5387. Haldane J (1895). The action of carbonic oxide on man. J Physiol 18, 430–462. Oliveira S, Queiroga CSF & Vieira HLA (2016). Mitochondria and carbon monoxide: cytoprotection and control of cell metabolism – a role for Ca2+ ? J Physiol 594, 4131–4138. Sjostrand T (1949). Endogenous formation of carbon monoxide in man. Nature 164, 580.
Additional information References
Competing interests
Almeida AS, Queiroga CSF, Sousa MFQ, Alves PM & Vieira HLA (2012). Carbon monoxide modulates apoptosis by reinforcing oxidative metabolism in astrocytes: Role of Bcl-2. J Biol Chem 287, 10761–10770. Elies J, Scragg JL, Boyle JP, Gamper N & Peers C (2016). Regulation of the T-type Ca2+ channel Cav3.2 by hydrogen sulfide: emerging controversies concerning the role of H2 S in nociception. J Physiol 594, 4119–4129.
None declared.
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
J Physiol 594.15 (2016) pp 4117–4118
EDITORIAL
Gaseous regulation of Ca2+ homeostasis; for better or worse? Mark L. Dallas School of Pharmacy, University of Reading, Reading, RG6 6UB, UK
The Journal of Physiology
Email: [email protected]
Carbon monoxide (CO) and hydrogen sulfide (H2 S) are two gases well recognised for their toxic properties. Less well appreciated are their physiological functions within biological systems. To this end there has been a recent revival of interest in these so-called gasotransmitters and this has led to a greater understanding of their role in both physiology and pathology. It has also been suggested that they may be used to treat complex diseases. The idea of using toxic gases to treat human diseases would have seemed far-fetched to those researchers that trail blazed experiments looking at their endogenous production and function in the 1890s and again in the 1950s (Haldane, 1895; Sjostrand, 1949). As part of Physiology 2015; a symposium drew together scientists looking at the effects of the gasotransmitters on calcium signalling. The physiological role(s) of H2 S are diverse and published research to date indicates a diverse array of effects in a range of cell types. Elies et al. (2016) report on the effects of H2 S on the voltage gated calcium channel subfamily Cav3 (T-type), responsible for an array of cellular processes and implicated in nociception. Using the hydrogen sulfide salt NaHS, they previously reported isoform specific inhibition of Cav3.2 channels (Elies et al. 2014). A clear demonstration of this isoform specificity was that mutation of the Cav3.2 redox and H2 S sensitive extracellular residue resulted in the loss of H2 S sensitivity, and introduction of this residue to the previously H2 S insensitive Cav3.1 produced a response to NaHS. There is debate about the chemical tools used in the H2 S field, with questions over physiological concentrations of H2 S and the microdomains of H2 S activity. The development of new donors offers targeted approaches; however, robust measurements of in vivo H2 S concentrations are still outstanding. The need to determine a range of physiological H2 S concentrations is of growing concern, given the wide
ranging and often conflicting reports being published in the gasotransmitter field. Elies et al. (2016) argue that NaHS mediated effects are through H2 S mediated redox modulation of the Cav3.2 channels and not via H2 S’s ability to chelate Zn2+ . However, manipulation of endogenous H2 S production (via cystathionine γ-lyase (CSE) and/or cystathionine β-synthetase (CBS)) would further their argument. In this instance it seems unlikely that physiological levels of H2 S (believed to be in the nanomolar range) will influence T-type channel activity in the process of nociception; however, more robust H2 S donors and manipulation of endogenous H2 S levels (e.g. transgenic animals) will provide a more definitive answer than is currently available. Furthermore, a clearer picture of the role that T-type channels play in regulating pain associated neurotransmission will clear up some of the ‘controversies’ to which Elies et al. allude. The underlying mechanisms by which CO benefits cellular physiology form an emerging research field and one that the Vieira group has contributed to (Oliveira et al. 2016). In this article Oliveira et al. describe the potential for CO to provide cytoprotection through modulation of cellular defence mechanisms. They point to mitochondria as key organelles in the ability of CO to confer anti-apoptotic properties. This may seem contradictory,
C O
given that previous studies have highlighted an increase in reactive oxygen species (ROS) under CO exposure. This reported increase in ROS is important for anti-inflammatory signalling and is also implicated in the cytotoxicity of CO. However, this is contrasted with the proposed antioxidant role that CO plays, which acts through reducing ROS production. Different molecular substrates are likely to underlie this dual action of CO; NADPH oxidases and cytochrome c oxidase have both been proposed. The level to which CO mediated ROS elevation is beneficial to cellular physiology is likely to be both cell and microenvironment specific. Here again Oliveira et al. bring in Ca2+ homeostasis which mediates mitochondrial function, through multiple cellular cascades (e.g. mitochondrial membrane permeabilisation). From a neuroscience perspective this opens up the potential for differential CO modulation of cellular metabolism (neurones vs. glia). Work from the Vieira group (Almeida et al. 2012) focused on astrocytes and demonstrated that CO prevents astrocyte apoptosis via stimulation of oxidative phosphorylation. However, the true extent of CO in astrocytes in situ remains to be determined. Cancer researchers are also looking to manipulate cell metabolic status with CO or haem oxgenase (HO) modulators; this could have implications for apopotosis of cancer cells or reducing
H
S
H
Ca2+
Figure 1. Schematic illustration of carbon monoxide and hydrogen sulfide effects on modulating calcium homeostasis highlighted in this edition of The Journal of Physiology Elies et al. (2016) highlight the influence of H2 S on T-type calcium channels, while Oliveira et al. (2016) point to effects of CO on the mitochondria to influence calcium.
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
DOI: 10.1113/JP272693
4118 the aggressive proliferative nature of cancer cells. While proposed cellular targets of CO are pertinent to cancer biology through their regulation of intracellular Ca2+ , a definitive approach to tackling cancer evades us. This may be in part due to a lack of understanding of CO biology and how to exploit it for therapeutic effect, or the numerous cancer types and their diverse pathology. A cautionary tale for those interested in CO biology is oxygen (O2 ) availability and the model systems that have illustrated a host of CO effects. It is known that hypoxia, or lack of O2 , induces the haem oxygenase 1 enzyme, thus stimulating haem breakdown to produce CO. In addition, O2 and CO compete for the same molecular targets (via haem binding motifs); this is also the case for nitric oxide. Therefore current in vitro approaches limit our physiological understandings of CO at a systems level; it is this that needs to be addressed to unravel the predominant role for CO in cellular metabolism. In an exciting and rapidly evolving field it remains to be seen if CO and H2 S will develop into therapeutics of the future.
Editorial At a physiological level there is still much to be learnt about these gases and their impact on cellular physiology. It does, however, seem clear that Ca2+ homeostasis underpins an array of both H2 S and CO cellular actions, as illustrated by Elies et al (2016) and Oliveira et al (2016) (Fig. 1). However, with current clinical trials looking at the effects of inhaled CO on cardiovascular disease (https:// clinicaltrials.gov/ct2/show/NCT01523548), the gasotransmitters may be used therapeutically sooner than once thought.
J Physiol 594.15
Elies J, Scragg JL, Huang S, Dallas ML, Huang D, MacDougall D, Boyle JP, Gamper N & Peers C (2014). Hydrogen sulfide inhibits Cav3.2 T-type Ca2+ channels. FASEB J 28, 5376–5387. Haldane J (1895). The action of carbonic oxide on man. J Physiol 18, 430–462. Oliveira S, Queiroga CSF & Vieira HLA (2016). Mitochondria and carbon monoxide: cytoprotection and control of cell metabolism – a role for Ca2+ ? J Physiol 594, 4131–4138. Sjostrand T (1949). Endogenous formation of carbon monoxide in man. Nature 164, 580.
Additional information References
Competing interests
Almeida AS, Queiroga CSF, Sousa MFQ, Alves PM & Vieira HLA (2012). Carbon monoxide modulates apoptosis by reinforcing oxidative metabolism in astrocytes: Role of Bcl-2. J Biol Chem 287, 10761–10770. Elies J, Scragg JL, Boyle JP, Gamper N & Peers C (2016). Regulation of the T-type Ca2+ channel Cav3.2 by hydrogen sulfide: emerging controversies concerning the role of H2 S in nociception. J Physiol 594, 4119–4129.
None declared.
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
