Bilirubin oxidation end products directly alter K+ channels important in the regulation of vascular tone.
The exact etiology of delayed cerebral vasospasm following cerebral hemorrhage is not clear, but a family of compounds termed 'bilirubin oxidation end products (BOXes)' derived from heme has been implicated. As proper regulation of vascular smooth muscle tone involves large-conductance Ca(2+)- and voltage-dependent Slo1 K(+) (BK, maxiK, K(Ca)1.1) channels, we examined whether BOXes altered functional properties of the channel. Electrophysiological measurements of Slo1 channels heterologously expressed in a human cell line and of native mouse BK channels in isolated cerebral myocytes showed that BOXes markedly diminished open probability. Biophysically, BOXes specifically stabilized the conformations of the channel with its ion conduction gate closed. The results of chemical amino-acid modifications and molecular mutagenesis together suggest that two specific lysine residues in the structural element linking the transmembrane ion-permeation domain to the carboxyl cytosolic domain of the Slo1 channel are critical in determining the sensitivity of the channel to BOXes. Inhibition of Slo1 BK channels by BOXes may contribute to the development of delayed cerebral vasospasm following brain hemorrhage.
Hou
Shangwei
S
Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Xu
Rong
R
Clark
Joseph F
JF
Wurster
William L
WL
Heinemann
Stefan H
SH
Hoshi
Toshinori
T
D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism; D001663:Bilirubin / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D055724:Electrophysiological Phenomena; D006801:Humans; D007700:Kinetics; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009129:Muscle Tonus / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D010084:Oxidation-Reduction; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D020301:Vasospasm, Intracranial / Q000503:physiopathology
C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D026902:Potassium Channel Blockers; D001663:Bilirubin