Published online before print September 15, 2005, doi: 10.1161/01.RES.0000186180.47148.7b
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Submitted on April 5, 2005
Revised on August 31, 2005
Accepted on September 6, 2005
Heme Is a Carbon Monoxide Receptor for Large-Conductance Ca2+-Activated K+ Channels
Jonathan H. Jaggar *;
From the Departments of Physiology (J.H.J., A.L., H.P., E.S.U., C.W.L.) and Pharmacology (J.L., A.M.D.), University of Tennessee Health Science Center, Memphis.
* To whom correspondence should be addressed. E-mail: jjaggar{at}physio1.utmem.edu.
Carbon monoxide (CO) is an endogenous paracrine and autocrine gaseous messenger that regulates physiological functions in a wide variety of tissues. CO induces vasodilation by activating arterial smooth muscle large-conductance Ca2+-activated potassium (BKCa) channels. However, the mechanism by which CO activates BKCa channels remains unclear. Here, we tested the hypothesis that CO activates BKCa channels by binding to channel-bound heme, a BKCa-channel inhibitor, and altering its inhibitory interaction with the conserved heme-binding domain (HBD) of the channel 
subunit C terminus. Data obtained using thin-layer chromatography, spectrophotometry, mass spectrometry (MS), and MS-MS indicate that CO modifies the binding of reduced heme to the subunit HBD. In contrast, CO does not alter the interaction between the HBD and oxidized heme (hemin), to which CO cannot bind. Consistent with these findings, electrophysiological measurements of native and cloned (cbv) cerebral artery smooth muscle BKCa channels show that CO reverses BKCa-channel inhibition by heme but not by hemin. Site-directed mutagenesis of the cbv HBD from CKACH to CKASR abolished both heme-induced channel inhibition and CO-induced activation. Furthermore, on binding CO, heme switches from being a channel inhibitor to an activator. These findings indicate that reduced heme is a functional CO receptor for BKCa channels, introduce a unique mechanism by which CO regulates the activity of a target protein, and reveal a novel process by which a gaseous messenger regulates ion channel activity.
Key words: vascular smooth muscle • vasodilation • potassium channels • signal transduction
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