Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels

Nature. 2003 Oct 2;425(6957):531-5. doi: 10.1038/nature02003.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Brain / drug effects
  • Brain / metabolism
  • Electrophysiology
  • Heme / metabolism*
  • Heme / pharmacology*
  • Hemin / metabolism
  • Hemin / pharmacology
  • Humans
  • Ion Channel Gating / drug effects
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Large-Conductance Calcium-Activated Potassium Channels
  • Molecular Sequence Data
  • Mutation
  • Oxidation-Reduction
  • Potassium Channels, Calcium-Activated / antagonists & inhibitors*
  • Potassium Channels, Calcium-Activated / chemistry
  • Potassium Channels, Calcium-Activated / genetics
  • Potassium Channels, Calcium-Activated / metabolism*
  • Protein Binding
  • Rats

Substances

  • KCNMA1 protein, human
  • Kcnma1 protein, rat
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Large-Conductance Calcium-Activated Potassium Channels
  • Potassium Channels, Calcium-Activated
  • Heme
  • Hemin