Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel.
Modulation of calcium-sensitive potassium (BK) channels by oxygen is important in several mammalian tissues, and in the carotid body it is crucial to respiratory control. However, the identity of the oxygen sensor remains unknown. We demonstrate that hemoxygenase-2 (HO-2) is part of the BK channel complex and enhances channel activity in normoxia. Knockdown of HO-2 expression reduced channel activity, and carbon monoxide, a product of HO-2 activity, rescued this loss of function. Inhibition of BK channels by hypoxia was dependent on HO-2 expression and was augmented by HO-2 stimulation. Furthermore, carotid body cells demonstrated HO-2-dependent hypoxic BK channel inhibition, which indicates that HO-2 is an oxygen sensor that controls channel activity during oxygen deprivation.
Williams
Sandile E J
SE
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
Wootton
Phillippa
P
Mason
Helen S
HS
Bould
Jonathan
J
Iles
David E
DE
Riccardi
Daniela
D
Peers
Chris
C
Kemp
Paul J
PJ
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D002344:Carotid Body / Q000166:cytology* / Q000502:physiology*; D015687:Cell Hypoxia; D002460:Cell Line; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008564:Membrane Potentials; D009249:NADP / Q000378:metabolism; D010100:Oxygen / Q000502:physiology*; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D014162:Transfection
C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D034741:RNA, Small Interfering; D006418:Heme; D009249:NADP; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D010100:Oxygen