Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels.
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.
Tang
Xiang Dong
XD
Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Xu
Rong
R
Reynolds
Mark F
MF
Garcia
Maria L
ML
Heinemann
Stefan H
SH
Hoshi
Toshinori
T
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D006418:Heme / Q000378:metabolism* / Q000494:pharmacology*; D006427:Hemin / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008969:Molecular Sequence Data; D009154:Mutation; D010084:Oxidation-Reduction; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats
C494841:KCNMA1 protein, human; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D006418:Heme; D006427:Hemin