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VASCULAR BIOLOGY

Calcium sparks activate calcium-dependent Cl^– current in rat corpus cavernosum smooth muscle cells

Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

Submitted 29 October 2006 ; accepted in final form 13 July 2007

Spontaneous transient currents, due to activation of Ca²⁺-dependent K⁺ and Cl^– channels, occur in corpus cavernosum smooth muscle cells (CCSMC) of the penis. The Ca²⁺ events responsible for triggering Ca²⁺-dependent Cl^– channels have never been identified in vascular muscle. We used high-speed fluorescence imaging combined with patch-clamp electrophysiology to provide the first characterization of Ca²⁺ events underlying these currents. Freshly isolated rat CCSMC loaded with fluo-4 exhibited localized, spontaneous elevations of intracellular Ca²⁺ (Ca²⁺ sparks) in 57% of cells. There was an average of 6.4 ± 0.5 release sites/cell with a frequency of 0.9 ± 1 Hz/cell and peak amplitude F/F_o of 67 ± 10%. We addressed the controversy of whether these events are mediated by ryanodine or inositol 1,4,5 trisphosphate (IP₃) receptors. Caffeine caused either a global Ca²⁺ rise at high concentrations or an increase in spark frequency at lower concentrations, whereas ryanodine dramatically reduced the amplitude and frequency of sparks. 2-Aminoethoxydiphenyl borate, an inhibitor of IP₃ receptors, had no effect on spark frequency. Combined imaging and electrophysiological recording revealed strong coupling between Ca²⁺ sparks and biphasic transient currents, a relationship never before shown in vascular muscle. Moreover, spark frequency increased on depolarization, an effect abolished with the blockade of Ca²⁺ channels, consistent with Ca²⁺ influx regulating Ca²⁺ release from stores. We establish for the first time that Ca²⁺ sparks occur in CCSMC and arise from Ca²⁺ release through ryanodine receptors. Moreover, the voltage dependence of spark frequency demonstrated here provides novel functional evidence for voltage-dependent Ca²⁺ influx in CCSMC.

calcium signaling; potassium and chloride channels; ryanodine receptors

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