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Mitochondrial Modulation of Ca²⁺-Induced Ca²⁺-Release in Rat Sensory Neurons

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota

Submitted 15 March 2006; accepted in final form 2 June 2006

Ca²⁺-induced Ca²⁺-release (CICR) from ryanodine-sensitive Ca²⁺ stores provides a mechanism to amplify and propagate a transient increase in intracellular calcium concentration ([Ca²⁺]_i). A subset of rat dorsal root ganglion neurons in culture exhibited regenerative CICR when sensitized by caffeine. [Ca²⁺]_i oscillated in the maintained presence of 5 mM caffeine and 25 mM K⁺. Here, CICR oscillations were used to study the complex interplay between Ca²⁺ regulatory mechanisms at the cellular level. Oscillations depended on Ca²⁺ uptake and release from the endoplasmic reticulum (ER) and Ca²⁺ influx across the plasma membrane because cyclopiazonic acid, ryanodine, and removal of extracellular Ca²⁺ terminated oscillations. Increasing caffeine concentration decreased the threshold for action potential-evoked CICR and increased oscillation frequency. Mitochondria regulated CICR by providing ATP and buffering [Ca²⁺]_i. Treatment with the ATP synthase inhibitor, oligomycin B, decreased oscillation frequency. When ATP concentration was held constant by recording in the whole cell patch-clamp configuration, oligomycin no longer affected oscillation frequency. Aerobically derived ATP modulated CICR by regulating the rate of Ca²⁺ sequestration by the ER Ca²⁺ pump. Neither CICR threshold nor Ca²⁺ clearance by the plasma membrane Ca²⁺ pump were affected by inhibition of aerobic metabolism. Uncoupling electron transport with carbonyl cyanide p-trifluoromethoxy-phenyl-hydrazone or inhibiting mitochondrial Na⁺/Ca²⁺ exchange with CGP37157 revealed that mitochondrial buffering of [Ca²⁺]_i slowed oscillation frequency, decreased spike amplitude, and increased spike width. These findings illustrate the interdependence of energy metabolism and Ca²⁺ signaling that results from the complex interaction between the mitochondrion and the ER in sensory neurons.

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