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Carbon monoxide activates K_Ca channels in newborn arteriole smooth muscle cells by increasing apparent Ca²⁺ sensitivity of -subunits

¹Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163; and ²Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557

Submitted 13 August 2003 ; accepted in final form 12 October 2003

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 µM) or CO released from dimanganese decacarbonyl (10 µM), 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 µM), 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 µM. Western blotting data suggested that the low Ca²⁺ sensitivity of newborn K_Ca channels may be due to a reduced -subunit-to--subunit ratio. CO activation of K_Ca channels was Ca²⁺ dependent. CO increased open probability 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- 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 -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.

patch-clamp electrophysiology; cerebrovascular circulation

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