Abstract
Haem is essential for living organisms, functioning as a crucial element in the redox-sensitive reaction centre in haemproteins. During the biogenesis of these proteins, the haem cofactor is typically incorporated enzymatically into the haem pockets of the apo-haemprotein as the functionally indispensable prosthetic group. A class of ion channel, the large-conductance calcium-dependent Slo1 BK channels, possesses a conserved haem-binding sequence motif. Here we present electrophysiological and structural evidence showing that haem directly regulates cloned human Slo1 channels and wild-type BK channels in rat brain. Both oxidized and reduced haem binds to the hSlo1 channel protein and profoundly inhibits transmembrane K+ currents by decreasing the frequency of channel opening. This direct regulation of the BK channel identifies a previously unknown role of haem as an acute signalling molecule.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Binding Sites
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Brain / drug effects
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Brain / metabolism
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Electrophysiology
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Heme / metabolism*
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Heme / pharmacology*
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Hemin / metabolism
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Hemin / pharmacology
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Humans
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Ion Channel Gating / drug effects
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
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Large-Conductance Calcium-Activated Potassium Channels
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Molecular Sequence Data
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Mutation
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Oxidation-Reduction
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Potassium Channels, Calcium-Activated / antagonists & inhibitors*
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Potassium Channels, Calcium-Activated / chemistry
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Potassium Channels, Calcium-Activated / genetics
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Potassium Channels, Calcium-Activated / metabolism*
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Protein Binding
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Rats
Substances
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KCNMA1 protein, human
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Kcnma1 protein, rat
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
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Large-Conductance Calcium-Activated Potassium Channels
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Potassium Channels, Calcium-Activated
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Heme
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Hemin