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Original Article

Functional Interaction of Inositol 1,4,5-Trisphosphate Receptors, Ryanodine Receptors, and Mitochondria

Stephen V. Straub^a, David R. Giovannucci^a, and David I. Yule^a

^a Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642
Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642.716-273-2652

david_giovannucci{at}urmc.rochester.edu

In pancreatic acinar cells, inositol 1,4,5-trisphosphate (InsP₃)–dependent cytosolic calcium ([Ca²⁺]_i) increases resulting from agonist stimulation are initiated in an apical "trigger zone," where the vast majority of InsP₃ receptors (InsP₃R) are localized. At threshold stimulation, [Ca²⁺]_i signals are confined to this region, whereas at concentrations of agonists that optimally evoke secretion, a global Ca²⁺ wave results. Simple diffusion of Ca²⁺ from the trigger zone is unlikely to account for a global [Ca²⁺]_i elevation. Furthermore, mitochondrial import has been reported to limit Ca²⁺ diffusion from the trigger zone. As such, there is no consensus as to how local [Ca²⁺]_i signals become global responses. This study therefore investigated the mechanism responsible for these events. Agonist-evoked [Ca²⁺]_i oscillations were converted to sustained [Ca²⁺]_i increases after inhibition of mitochondrial Ca²⁺ import. These [Ca²⁺]_i increases were dependent on Ca²⁺ release from the endoplasmic reticulum and were blocked by 100 µM ryanodine. Similarly, "uncaging" of physiological [Ca²⁺]_i levels in whole-cell patch-clamped cells resulted in rapid activation of a Ca²⁺-activated current, the recovery of which was prolonged by inhibition of mitochondrial import. This effect was also abolished by ryanodine receptor (RyR) blockade. Photolysis of D-myo InsP₃ P⁴⁽⁵⁾-1-(2-nitrophenyl)-ethyl ester (caged InsP₃) produced either apically localized or global [Ca²⁺]_i increases in a dose-dependent manner, as visualized by digital imaging. Mitochondrial inhibition permitted apically localized increases to propagate throughout the cell as a wave, but this propagation was inhibited by ryanodine and was not seen for minimal control responses resembling [Ca²⁺]_i puffs. Global [Ca²⁺]_i rises initiated by InsP₃ were also reduced by ryanodine, limiting the increase to a region slightly larger than the trigger zone. These data suggest that, while Ca²⁺ release is initially triggered through InsP₃R, release by RyRs is the dominant mechanism for propagating global waves. In addition, mitochondrial Ca²⁺ import controls the spread of Ca²⁺ throughout acinar cells by modulating RyR activation.

Key Words: calcium dynamics • intracellular signaling • exocrine cells • flash photolysis • digital imaging

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