Modulation of ion channels and transporters by carbon monoxide: causes for concern?

Heme oxygenases, particularly the inducible heme oxygenase-1 (HO-1), are the subject of intensive research since they show great promise as cytoprotective agents. These enzymes degrade heme to generate biliverdin, free iron, and carbon monoxide (CO), and this reaction appears to be crucial in a number of diverse biological systems. Decreasing free heme in itself is beneficial [for example in sepsis and infections (Gozzelino et al., 2010)], but much attention is also paid to the products of heme degradation as biologically active agents with therapeutic potential (Motterlini and Otterbein, 2010; Wegiel et al., 2012). Indeed, the physiological roles and potential of CO in particular (applied either by inhalation, or via CO releasing molecules; CORMs) are currently topics of intense research, with clinical trials currently evaluating its safety in human subjects and its usefulness in treating a variety of disorders (http://clinicaltrials.gov/ct2/search, “carbon monoxide”) (Wu and Wang, 2005; Durante et al., 2006; Kim et al., 2006; Ryter et al., 2006).

In this current climate of hopeful promise for CO-based therapies, it is easy to lose sight of the fact that it is a highly toxic gas: CO poisoning accounts for more than 50% of all fatal poisonings worldwide (Meredith and Vale, 1988; Cobb and Etzel, 1991; Varon et al., 1999). Although the number of fatalities arising from acute exposure may be considered relatively low, chronic exposure can much more commonly produce neurological and cardiovascular damage (Von Burg, 1999; Gandini et al., 2001; Omaye, 2002; Prockop and Chichkova, 2007), particularly in the aging population, and symptoms are often difficult to diagnose (Harper and Croft-Baker, 2004). Appropriately, therefore, much caution is taken as clinical trials progress and as our awareness of the biological actions of CO continues to develop.

In recent years, ion channels (and, more recently, transporters) have emerged as major targets for modulation by CO (Peers, 2011; Wilkinson and Kemp, 2011; Peers and Steele, 2012). Intriguingly, modulation of some channels by CO may contribute to its beneficial actions, yet the sensitivity of other channels to CO may account, at least in part, for some of its deleterious actions (summarized in Figure 1). In this article, I draw upon some recent examples of ion channel/transporter modulation by CO in the cardiovascular and central nervous systems in order to compare the beneficial and deleterious cellular effects of CO, and to examine whether we should be concerned about the therapeutic index of CO.