This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 97/8/805    most recent 01.RES.0000186180.47148.7bv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jaggar, J. H. Articles by Leffler, C. W. Search for Related Content PubMed PubMed Citation Articles by Jaggar, J. H. Articles by Leffler, C. W. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CARBON MONOXIDE OXYGEN Related Collections Cell signalling/signal transduction Ion channels/membrane transport Other Vascular biology

(Circulation Research. 2005;97:805.)
© 2005 American Heart Association, Inc.

Cellular Biology

Heme Is a Carbon Monoxide Receptor for Large-Conductance Ca²⁺-Activated K⁺ Channels

Jonathan H. Jaggar, Anlong Li, Helena Parfenova, Jianxi Liu, Edward S. Umstot, Alejandro M. Dopico, Charles W. Leffler

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.

Correspondence to Jonathan H. Jaggar, Dept of Physiology, Univ of Tennessee Health Science Center, Nash Bldg, 894 Union Ave, Memphis, TN 38139. 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 (BK_Ca) channels. However, the mechanism by which CO activates BK_Ca channels remains unclear. Here, we tested the hypothesis that CO activates BK_Ca channels by binding to channel-bound heme, a BK_Ca channel inhibitor, and altering the interaction between heme and 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 BK_Ca channels show that CO reverses BK_Ca 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 BK_Ca 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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