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Am J Physiol Cell Physiol. 2007 Jun;292(6):C2122-8. Epub 2007 Feb 21.

Hypoxia reduces KCa channel activity by inducing Ca2+ spark uncoupling in cerebral artery smooth muscle cells.

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Dept. of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.


Arterial smooth muscle cell large-conductance Ca(2+)-activated potassium (K(Ca)) channels have been implicated in modulating hypoxic dilation of systemic arteries, although this is controversial. K(Ca) channel activity in arterial smooth muscle cells is controlled by localized intracellular Ca(2+) transients, termed Ca(2+) sparks, but hypoxic regulation of Ca(2+) sparks and K(Ca) channel activation by Ca(2+) sparks has not been investigated. We report here that in voltage-clamped (-40 mV) cerebral artery smooth muscle cells, a reduction in dissolved O(2) partial pressure from 150 to 15 mmHg reversibly decreased Ca(2+) spark-induced transient K(Ca) current frequency and amplitude to 61% and 76% of control, respectively. In contrast, hypoxia did not alter Ca(2+) spark frequency, amplitude, global intracellular Ca(2+) concentration, or sarcoplasmic reticulum Ca(2+) load. Hypoxia reduced transient K(Ca) current frequency by decreasing the percentage of Ca(2+) sparks that activated a transient K(Ca) current from 89% to 63%. Hypoxia reduced transient K(Ca) current amplitude by attenuating the amplitude relationship between Ca(2+) sparks that remained coupled and the evoked transient K(Ca) currents. Consistent with these data, in inside-out patches at -40 mV hypoxia reduced K(Ca) channel apparent Ca(2+) sensitivity and increased the K(d) for Ca(2+) from approximately 17 to 32 microM, but did not alter single-channel amplitude. In summary, data indicate that hypoxia reduces K(Ca) channel apparent Ca(2+) sensitivity via a mechanism that is independent of cytosolic signaling messengers, and this leads to uncoupling of K(Ca) channels from Ca(2+) sparks. Transient K(Ca) current inhibition due to uncoupling would oppose hypoxic cerebrovascular dilation.

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