Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 286, Issue 2, Pages H610-H618Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00782.2003
Keywords
patch-clamp electrophysiology; cerebrovascular circulation
Funding
- NHLBI NIH HHS [HL-034059, HL-042851, R01 HL034059] Funding Source: Medline
- NINDS NIH HHS [NS-67061] Funding Source: Medline
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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 large-conductance Ca2+-activated K+ (K-Ca) channels in newborn porcine cerebral arteriole smooth muscle cells. In intact cells at 0 mV, CO (3 muM) or CO released from dimanganese decacarbonyl (10 muM), a novel light-activated CO donor, increased K-Ca channel activity 4.9- or 3.5-fold, respectively. K-Ca channel activation by CO was not blocked by 1-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (25 muM), a soluble guanylyl cyclase inhibitor. In inside-out patches at 0 mV, CO shifted the Ca2+ concentration-response curve for K-Ca channels leftward and decreased the apparent dissociation constant for Ca2+ from 31 to 24 muM. Western blotting data suggested that the low Ca2+ sensitivity of newborn K-Ca channels may be due to a reduced beta-subunit-to-alpha-subunit ratio. CO activation of K-Ca channels was Ca2+ dependent. CO increased open probability 3.7-fold with 10 muM 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 HEK-293 cells, increasing currents 2.2-fold at + 50 mV. In summary, data suggest that in newborn arteriole smooth muscle cells, CO activates low-affinity K-Ca 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 K-Ca channels will lead to preferential activation by signaling modalities, such as Ca2+ sparks, which elevate the subsarcolemmal Ca2+ concentration within this range.
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