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Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee
Submitted 21 November 2005 ; accepted in final form 17 January 2006
L-type, voltage-dependent calcium (Ca2+) channels, ryanodine-sensitive Ca2+ release (RyR) channels, and large-conductance Ca2+-activated potassium (KCa) channels comprise a functional unit that regulates smooth muscle contractility. Here, we investigated whether genetic ablation of caveolin-1 (cav-1), a caveolae protein, alters Ca2+ spark to KCa channel coupling and Ca2+ spark regulation by voltage-dependent Ca2+ channels in murine cerebral artery smooth muscle cells. Caveolae were abundant in the sarcolemma of control (cav-1+/+) cells but were not observed in cav-1-deficient (cav-1–/–) cells. Ca2+ spark and transient KCa current frequency were approximately twofold higher in cav-1–/– than in cav-1+/+ cells. Although voltage-dependent Ca2+ current density was similar in cav-1+/+ and cav-1–/– cells, diltiazem and Cd2+, voltage-dependent Ca2+ channel blockers, reduced transient KCa current frequency to 
55% of control in cav-1+/+ cells but did not alter transient KCa current frequency in cav-1–/– cells. Furthermore, although KCa channel density was elevated in cav-1–/– cells, transient KCa current amplitude was similar to that in cav-1+/+ cells. Higher Ca2+ spark frequency in cav-1–/– cells was not due to elevated intracellular Ca2+ concentration, sarcoplasmic reticulum Ca2+ load, or nitric oxide synthase activity. Similarly, Ca2+ spark amplitude and spread, the percentage of Ca2+ sparks that activated a transient KCa current, the amplitude relationship between sparks and transient KCa currents, and KCa channel conductance and apparent Ca2+ sensitivity were similar in cav-1+/+ and cav-1–/– cells. In summary, cav-1 ablation elevates Ca2+ spark and transient KCa current frequency, attenuates the coupling relationship between voltage-dependent Ca2+ channels and RyR channels that generate Ca2+ sparks, and elevates KCa channel density but does not alter transient KCa current activation by Ca2+ sparks. These findings indicate that cav-1 is required for physiological Ca2+ spark and transient KCa current regulation in cerebral artery smooth muscle cells.
ryanodine-sensitive Ca2+ release channel; large-conductance Ca2+-activated potassium channel; caveolae; voltage-dependent Ca2+ channel
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