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 Me Ca2+. releaser inositol 1,4,5-trisphosphate (IP3) has been associated with diverse cell functions. Yet, the physiological sig nificance of IP3 in tissues that feature a ryanodine-sensitive sarcoplasmic reticulum has remained elusive. IP3 generated by photolysis of caged IP3 o r by purinergic activation of phospholipase C gamma slowed down or abolishe d autonomic Ca2+ spiking hi neonatal rat cardiomyocytes. Microinjection of heparin, blocking dominant-negative fusion protein, or anti-phospholipase C gamma antibody prevented the IP3-mediated purinergic effect. IP3 triggered a ryanodine- and caffeine-insensitive Ca2+ release restricted to the perin uclear region. In cells loaded with Rhod2 or expressing a mitochondria-targ eted cameleon and TMRM to monitor mitochondrial Ca2+ and potential, IP3 ind uced transient Ca2+ loading and depolarization of the organelles. These mit ochondrial changes were associated with Ca2+ depletion of the sarcoplasmic reticulum and preceded the arrest of cellular Ca2+ spiking. Thus, IP3 actin g within a restricted cellular region regulates the dynamic of calcium flow between mitochondria and the endoplasmic/sarcoplasmic reticulum. We have t hus uncovered a novel role for IP3 in excitable cells, the regulation of ca rdiac autonomic activity.