Inositol 1,4,5-Trisphosphate Directs Ca2+Flow between Mitochondria and the Endoplasmic/Sarcoplasmic Reticulum: A Role in Regulating Cardiac Autonomic Ca2+Spiking

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Abstract
The signaling role of the Ca2+releaser inositol 1,4,5-trisphosphate (IP3) has been associated with diverse cell functions. Yet, the physiological significance of IP3in tissues that feature a ryanodine-sensitive sarcoplasmic reticulum has remained elusive. IP3generated by photolysis of caged IP3or by purinergic activation of phospholipase Cγ slowed down or abolished autonomic Ca2+spiking in neonatal rat cardiomyocytes. Microinjection of heparin, blocking dominant-negative fusion protein, or anti-phospholipase Cγ antibody prevented the IP3-mediated purinergic effect. IP3triggered a ryanodine- and caffeine-insensitive Ca2+release restricted to the perinuclear region. In cells loaded with Rhod2 or expressing a mitochondria-targeted cameleon and TMRM to monitor mitochondrial Ca2+and potential, IP3induced transient Ca2+loading and depolarization of the organelles. These mitochondrial changes were associated with Ca2+depletion of the sarcoplasmic reticulum and preceded the arrest of cellular Ca2+spiking. Thus, IP3acting within a restricted cellular region regulates the dynamic of calcium flow between mitochondria and the endoplasmic/sarcoplasmic reticulum. We have thus uncovered a novel role for IP3in excitable cells, the regulation of cardiac autonomic activity.