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Am J Physiol Heart Circ Physiol (October 16, 2003). doi:10.1152/ajpheart.00782.2003
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Submitted on August 13, 2003
Accepted on October 12, 2003

Carbon monoxide activates KCa channels in newborn arteriole smooth muscle cells by increasing the apparent Ca2+ sensitivity of the {alpha}-subunit

Qi Xi1, Dilyara Tcheranova1, Helena Parfenova1, Burton Horowitz2, Charles W. Leffler1, and Jonathan H. Jaggar1*

1 Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA
2 Department of Physiology and Cell Biology, University of Nevada, Reno, NV, USA

* To whom correspondence should be addressed. E-mail: jjaggar{at}physio1.utmem.edu.

Carbon monoxide (CO) is a gaseous vasodilator produced by many cell types, including endothelial and smooth muscle cells. The goal of the present study was to investigate signaling mechanisms responsible for CO activation of KCa channels in newborn porcine cerebral arteriole smooth muscle cells. In intact cells at 0 mV, CO (3 µM), or CO released from dimanganese decacarbonyl (DMDC, 10 µM), a novel light-activated CO donor, increased KCa channel activity 4.9-fold or 3.5-fold, respectively. KCa channel activation by CO was not blocked by ODQ (25 µM), a soluble guanylyl cyclase inhibitor. In inside-out patches at 0 mV, CO shifted the Ca2+-concentration response curve for KCa channels leftward and decreased the apparent dissociation constant (Kd) for Ca2+ from 31 to 24 µM. Western blotting data suggested that the low Ca2+-sensitivity of newborn KCa channels may be due to a reduced {beta} / {alpha} subunit ratio. CO activation of KCa channels was Ca2+-dependent. CO increased open probability (Po) 3.7-fold with 10 µM free Ca2+ at the cytosolic membrane surface, but only 1.1-fold with 300 nM Ca2+. CO left shifted the current-voltage relationship of cslo-{alpha} currents expressed in HEK293 cells, increasing currents 2.2-fold at +50 mV. In summary, data suggest that in newborn arteriole smooth muscle cells, CO activates low-affinity KCa channels via a direct effect on the {alpha}-subunit that increases apparent Ca2+ sensitivity. The optimal tuning by CO of the micromolar Ca2+ sensitivity of KCa channels will lead to preferential activation by signaling modalities, such as Ca2+ sparks, that elevate the sub-sarcolemmal Ca2+ concentration within this range.




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