channels as Bioscience effectors in carbon monoxide signaling [Communicative & Integrative Biology 2:3, 241-242; May/June 2009]; Ion ©2009 Landes
Article Addendum
Ion channels as effectors in carbon monoxide signaling Chris Peers,* Mark L. Dallas and Jason L. Scragg Division of Cardiovascular and Neuronal Remodelling; Faculty of Medicine and Health; University of Leeds; Leeds, UK
Key words: Ion channel, carbon monoxide, heme oxygenase, reactive oxygen species, hypoxia, mitochondria
A wealth of recent studies has highlighted the diverse and important influences of carbon monoxide (CO) on cellular signaling pathways. Such studies have implicated CO, and the enzymes from which it is derived (heme oxygenases) as potential therapeutic targets, particularly (although not exclusively) in inflammation, immunity and cardiovascular disease.1 In a recent study,2 we demonstrated that CO inhibited cardiac L-type Ca2+ channels. This effect arose due to the ability of CO to bind to mitochondria (presumably at complex IV of the electron transport chain) and so cause electron leak, which resulted in increased production of reactive oxygen species. These modulated the channel’s activity through interactions with three cysteine residues in the cytosolic C-terminus of the channel’s major, pore-forming subunit. Our study provided a potential mechanism for the cardioprotective effects of CO and also highlighted ion channels as a major potential target group for this gasotransmitter. Carbon monoxide (CO) is well known as a highly toxic gas, due to its ability to bind strongly to haemoglobin and so prevent O2 transport and delivery. However, it is now also well established that endogenous CO is an important autocrine/paracrine regulator of cell function.3,4 CO is formed primarily by the actions of two heme oxygenases, the inducible HO-1 and the constitutively expressed HO-2. In the presence of O2 and NADPH, both enzymes catabolize heme to generate ferrous iron (Fe2+), CO and biliverdin, which are rapidly reduced to the antioxidant bilirubin. This reaction is crucial to iron and bile metabolism and cellular redox status in addition to forming CO. The diverse array of signaling pathways that can be modulated by CO (Fig. 1) have led to the realization that it is an important regulator of numerous cellular processes in a wide variety of tissues. CO has been known to modulate ion channels for many years,5 but such *Correspondence to: Chris Peers; Division of Cardiovascular and Neuronal Remodelling; Faculty of Medicine and Health; Worsley Building (Level 10); University of Leeds; Clarendon Way; Leeds LS2 9JT UK; Tel.: +441133434174; Fax: +441133434803; Email:
[email protected] Submitted: 02/09/09; Accepted: 02/10/09 Previously published online as a Communicative & Integrative Biology E-publication: http://www.landesbioscience.com/journals/cib/article/8158 Addendum to: Scragg JL, Dallas ML, Wilkinson JA, Varadi G, Peers C. Carbon monoxide inhibits L-type Ca2+ channels via redox modulation of key cysteine residues by mitochondrial reactive oxygen species. J Biol Chem 2008; 283:24412–9; PMID: 18596041; DOI: 10.1074/jbc.M803037200. www.landesbioscience.com
Figure 1. Schematic illustrating the synthesis and effects of carbon monoxide (CO). CO is generated by the O2 and NADPH-dependent catabolism of heme by HO-1 and HO-2. CO can stimulate or inhibit a number of signalling pathways, as illustrated. Of particular relevance to our studies, CO can bind to complex IV of the mitochondrial electron transport chain, leading to electron leak from complex III. This permits increased production of reactive oxygen species (ROS) that in turn leads to modulation of L-type Ca2+ channel activity via interaction with three cysteine residues located in the cytoplasmic C-terminal of the channel’s α subunit.
activity was more recently highlighted when it was found to mediate the O2 sensitivity of BKCa channels in the O2 sensing carotid body. Thus, HO-2 was found to co-localize with BKCa channels and— under normoxic conditions—sustain their activity through tonic production of CO. In hypoxia, channel activity declined (since CO production is O2 dependent). Thus, ironically, our ability to sense an essential gas appeared dependent on the production of a toxic one.6 Since O2 sensitive ion channels have been widely reported,7 we investigated whether CO might also regulate other O2 sensitive channels, and focused on the cardiovascular system. CO has been established as an important signaling molecule in both the heart and vasculature. Cardiac myocytes express HO-1 and HO-2, and HO-1 levels can be increased by various stresses8 including myocardial infarction.9 CO limits the damage of cardiac ischemia/reperfusion injury.10 Indeed, such injury is greater in HO-1 knockout mice.11 Conversely, cardiac HO-1 overexpression reduces ischemia/reperfusion injury.11 In addition, CO improves cardiac blood supply
Communicative & Integrative Biology
241
Ion channels as effectors in carbon monoxide signaling
through dilation of coronary vessels12,13 and, indeed, its ability to dilate blood vessels is long established (reviewed in ref. 14). Central to cardiac and vascular smooth muscle function is the regulation of [Ca2+]i, in particular Ca2+ entry through voltage-gated L-type Ca2+ channels. Since such channels were known to be O2 sensitive,15,16 we recently investigated the potential regulation of such channels by CO.2 Figure 1 illustrates the mechanism by which CO regulates L-type Ca2+ channels. In brief, CO acts at mitochondria (presumably by interacting at complex IV (reviewed in ref. 17), causing electron leak specifically from complex III. Such leak leads to rapid formation of reactive oxygen species which cause channel inhibition through a specific interaction with three cysteine residues in the C-terminal tail of the channel’s major subunit.2 Importantly, CO leads to channel inhibition, so it cannot account for inhibition by hypoxia via the same mechanism as modulation of BKCa channels,6 since that would predict CO enhances Ca2+ currents. However, our finding provides a potential mechanism of cardioprotection following cardiac insults (e.g., ischemia, see above), which stimulate HO-1 induction. The resultant CO produced could reduce Ca2+ influx via L-type Ca2+ channels and thereby reduce the cellular energy demands required for contraction. Our study has implications beyond cardioprotection, since it identifies the L-type Ca2+ channel as a new target molecule regulated by CO. The influence of this gasotransmitter is increasingly recognized as important and widespread: it now appears that ion channels may be a major new target group for some of its actions.
16. Fearon IM, Varadi G, Koch S, Isaacsohn I, Ball SG, Peers C. Splice variants reveal the region involved in oxygen sensing by recombinant human L-type Ca2+ channels. Circ Res 2000; 87:537-9. 17. D’Amico G, Lam F, Hagen T, Moncada S. Inhibition of cellular respiration by endogenously produced carbon monoxide. J Cell Sci 2006; 119:2291-8.
Acknowledgements
This work was supported by the British Heart Foundation and Wellcome Trust. References 1. Scott JR, Chin BY, Bilban MH, Otterbein LE. Restoring homeostasis: is heme oxygenase-1 ready for the clinic? Trends Pharmacol Sci 2007; 28:200-5. 2. Scragg JL, Dallas ML, Wilkinson JA, Varadi G, Peers C. Carbon monoxide inhibits L-type Ca2+ channels via redox modulation of key cysteine residues by mitochondrial reactive oxygen species. J Biol Chem 2008; 283:24412-9. 3. Kim HP, Ryter SW, Choi AM. CO as a cellular signaling molecule. Annu Rev Pharmacol Toxicol 2006; 46:411-49. 4. Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 2006; 86:583-650. 5. Wu L, Wang R. Carbon monoxide: endogenous production, physiological functions and pharmacological applications. Pharmacol Rev 2005; 57:585-630. 6. Williams SE, Wootton P, Mason HS, Bould J, Iles DE, Riccardi D, et al. Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science 2004; 306:2093-7. 7. Kemp PJ, Peers C. Oxygen sensing by ion channels. Essays Biochem 2007; 43:77-90. 8. Ewing JF, Raju VS, Maines MD. Induction of heart heme oxygenase-1 (HSP32) by hyperthermia: possible role in stress-mediated elevation of cyclic 3':5'-guanosine monophosphate. J Pharmacol Exp Ther 1994; 271:408-14. 9. Lakkisto P, Palojoki E, Backlund T, Saraste A, Tikkanen I, Voipio-Pulkki LM, et al. Expression of heme oxygenase-1 in response to myocardial infarction in rats. J Mol Cell Cardiol 2002; 34:1357-65. 10. Clark JE, Naughton P, Shurey S, Green CJ, Johnson TR, Mann BE, et al. Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res 2003; 93:2-8. 11. Yet SF, Tian R, Layne MD, Wang ZY, Maemura K, Solovyeva M, et al. Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res 2001; 89:168-73. 12. Grilli A, De Lutiis MA, Patruno A, Speranza L, Gizzi F, Taccardi AA, et al. Inducible nitric oxide synthase and heme oxygenase-1 in rat heart: direct effect of chronic exposure to hypoxia. Ann Clin Lab Sci 2003; 33:208-15. 13. McGrath JJ. The effects of carbon monoxide on the heart: an in vitro study. Pharmacol Biochem Behav 1984; 21:99-102. 14. Durante W, Johnson FK, Johnson RA. Role of carbon monoxide in cardiovascular function. J Cell Mol Med 2006; 10:672-86. 15. Fearon IM, Palmer ACV, Balmforth AJ, Ball SG, Mikala G, Schwartz A, et al. Hypoxia inhibits the recombinant a1C subunit of the human cardiac L-type Ca2+ channel. J Physiol 1997; 500:551-6. 242
Communicative & Integrative Biology
2009; Vol. 2 Issue 3
