Inositol 1,4,5-trisphosphate directs Ca²⁺ flow between mitochondria and the endoplasmic/sarcoplasmic reticulum: A role in regulating cardiac autonomic Ca²⁺ spiking

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 IP₃ in tissues that feature a ryanodine- sensitive sarcoplasmic reticulum has remained elusive. IP₃ generated by photolysis of caged IP₃ or 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. IP₃ triggered 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, IP₃ induced 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, IP₃ acting 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 IP₃ in excitable cells, the regulation of cardiac autonomic activity.