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¹ Department of Biomedical Sciences, College of Veterinary Medicine, and ² Department of Engineering and Applied Physics, College of Engineering, Cornell University, Ithaca, NY 14850

Correspondence to Michael I. Kotlikoff: mik7{at}cornell.edu

Ca²⁺-induced Ca²⁺ release (CICR) from the sarcoplasmic reticulum (SR) occurs in smooth muscle as spontaneous SR Ca²⁺ release or Ca²⁺ sparks and, in some spiking tissues, as Ca²⁺ release that is triggered by the activation of sarcolemmal Ca²⁺ channels. Both processes display spatial localization in that release occurs at a higher frequency at specific subcellular regions. We have used two-photon flash photolysis (TPFP) of caged Ca²⁺ (DMNP-EDTA) in Fluo-4–loaded urinary bladder smooth muscle cells to determine the extent to which spatially localized increases in Ca²⁺ activate SR release and to further understand the molecular and biophysical processes underlying CICR. TPFP resulted in localized Ca²⁺ release in the form of Ca²⁺ sparks and Ca²⁺ waves that were distinguishable from increases in Ca²⁺ associated with Ca²⁺ uncaging, unequivocally demonstrating that Ca²⁺ release occurs subsequent to a localized rise in [Ca²⁺]_i. TPFP-triggered Ca²⁺ release was not constrained to a few discharge regions but could be activated at all areas of the cell, with release usually occurring at or within several microns of the site of photolysis. As expected, the process of CICR was dominated by ryanodine receptor (RYR) activity, as ryanodine abolished individual Ca²⁺ sparks and evoked release with different threshold and kinetics in FKBP12.6-null cells. However, TPFP CICR was not completely inhibited by ryanodine; Ca²⁺ release with distinct kinetic features occurred with a higher TPFP threshold in the presence of ryanodine. This high threshold release was blocked by xestospongin C, and the pharmacological sensitivity and kinetics were consistent with CICR release at high local [Ca²⁺]_i through inositol trisphosphate (InsP₃) receptors (InsP₃Rs). We conclude that CICR activated by localized Ca²⁺ release bears essential similarities to those observed by the activation of I_Ca (i.e., major dependence on the type 2 RYR), that the release is not spatially constrained to a few specific subcellular regions, and that Ca²⁺ release through InsP₃R can occur at high local [Ca²⁺]_i.

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