Mechanistic Insight into the Heme-independent Interplay between Iron and Carbon Monoxide in CFTR and Slo1 BK _Ca Channels

Abstract

Ion channels have been extensively reported as an effector of carbon monoxide (CO). However, the mechanisms of heme-independent CO action are still missing. Because most of ion channels are heterologously expressed on human embryonic kidney cells which are cultured in Fe ³⁺-containing media, CO may act as a small and strong iron chelator to disrupt a putative iron bridge in ion channels and thus to tune their activity. In this review CFTR and Slo1 BK _Ca channels are employed to discuss the possible heme-independent interplay between iron and CO. Our recent studies demonstrated a high-affinity Fe ³⁺ site at the interface between the regulatory domain and intracellular loop 3 of CFTR. Because the binding of Fe ³⁺ to CFTR prevents channel opening, the stimulatory effect of CO on the Cl ⁻ and HCO ₃ ⁻ currents across the apical membrane of rat distal colon may be due to the release of inhibitive Fe ³⁺ by CO. In contrast, CO repeatedly stimulates the human Slo1 BK _Ca channel opening possibly by binding to an unknown iron site because cyanide prohibits this heme-independent CO stimulation. Here, in silico research on recent structural data of the slo1 BK _Ca channels indicates two putative binuclear Fe ²⁺-binding motifs in the gating ring in which CO may compete with protein residues to bind to either Fe ²⁺ bowl to disrupt the Fe ²⁺ bridge but not to release Fe ²⁺ from the channel. Thus, these two new regulation models of CO, iron releasing from and retaining in the ion channel, may have significant and extensive implications for other metalloproteins.