![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication January 22, 2007.
Revised March 23, 2007.
Accepted for publication April 27, 2007.
1 (KCNMB1)-subunits mediate
lithocholate activation of BK channels and dilation in
small, resistance arteries
Among the nongenomic effects of steroids, control of
vasomotion has received increasing attention.
Lithocholate (LC) and other physiologically relevant
cholane-derived steroids cause vasodilation, yet the
molecular targets and mechanisms underlying this action
remain largely unknown. We demonstrate that LC (45 µ
M) reversibly increases the diameter of pressurized
resistance cerebral arteries by ~10%, which would result
in ~30% increase in cerebral blood flow. LC action is
independent of endothelial integrity, prevented by 55 nM
iberiotoxin, and unmodified by 0.8 mM 4-aminopyridine,
indicating that LC causes vasodilation via
myocyte BK channels. Indeed, LC activates BK channels in
isolated myocytes through a destabilization of channel
long-closed states without modifying unitary
conductance. LC channel activation occurs within a wide
voltage range and at Ca2+ concentrations
reached in the myocyte whether at rest or during
contraction. Channel accessory 
1-
subunits, which are predominant in smooth muscle, are
necessary for LC to modify channel activity. In
contrast, 4-subunits, which are
predominant in neuronal tissues, fail to evoke LC
sensitivity. LC activation of cbv1+1
and native BK channels display identical
characteristics, including EC50 (46 µM)
and Emax (
300 µM), strongly suggesting
that the cbv1+1 complex is necessary
and sufficient to evoke LC action. Finally, intact
arteries from 1-subunit knockout mice
fail to relax in response to LC, although they are able
to respond to other vasoactive agents. This study
pinpoints the BK 1-subunit as the
molecule that senses LC, which results in myocyte BK
channel activation and, thus, endothelial-independent
relaxation of small, resistance arteries.
Key words:
Ion channel regulation, Calcium (Votage-Gated Channels), Potassium, Func. analysis receptor/ion channel mutants, Single channel kinetics, Structure/function/mechanism, Ischemia/Reperfusion
This article has been cited by other articles:
|
|
 |
|
  N. J. Rusch BK channels in cardiovascular disease: a complex story of channel dysregulation Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1580 - H1582. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tong and R. K. Duncan Tamoxifen inhibits BK channels in chick cochlea without alterations in voltage-dependent activation Am J Physiol Cell Physiol, July 1, 2009; 297(1): C75 - C85. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hou, S. H. Heinemann, and T. Hoshi Modulation of BKCa Channel Gating by Endogenous Signaling Molecules Physiology, February 1, 2009; 24(1): 26 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. N. Bukiya, J. McMillan, A. L. Parrill, and A. M. Dopico Structural determinants of monohydroxylated bile acids to activate {beta}1 subunit-containing BK channels J. Lipid Res., November 1, 2008; 49(11): 2441 - 2451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Liu, T. Vaithianathan, K. Manivannan, A. Parrill, and A. M. Dopico Ethanol Modulates BKCa Channels by Acting as an Adjuvant of Calcium Mol. Pharmacol., September 1, 2008; 74(3): 628 - 640. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Vaithianathan, A. Bukiya, J. Liu, P. Liu, M. Asuncion-Chin, Z. Fan, and A. Dopico Direct Regulation of BK Channels by Phosphatidylinositol 4,5-Bisphosphate as a Novel Signaling Pathway J. Gen. Physiol., July 1, 2008; 132(1): 13 - 28. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
