Yang, Z, Kirton, HM, MacDougall, DA et al. (9 more authors) (2015) The Golgi apparatus is a functionally distinct Ca2+ store regulated by the PKA and Epac branches of the β1-adrenergic signaling pathway. Science Signaling, 8 (398). ra101. ISSN 1945-0877
Abstract
Ca²+ release from the Golgi apparatus regulates key functions of the organelle, including vesicle trafficking. We found that the Golgi apparatus was the source of prolonged Ca²+ release events that originated near the nuclei of primary cardiomyocytes. Golgi Ca²+ release was unaffected by depletion of sarcoplasmic reticulum Ca²+, and disruption of the Golgi apparatus abolished Golgi Ca²+ release without affecting sarcoplasmic reticulum function, suggesting functional and spatial independence of Golgi and sarcoplasmic reticulum Ca²+ stores. β₁-Adrenoceptor stimulation triggers the production of the second messenger cAMP, which activates the Epac family of Rap guanine nucleotide exchange factors and the kinase PKA (protein kinase A). Phosphodiesterases (PDEs), including those in the PDE3 and PDE4 families, degrade cAMP. Activation of β1-adrenoceptors stimulated Golgi Ca²+ release, an effect that required activation of Epac, PKA, and the kinase CaMKII. Inhibition of PDE3s or PDE4s potentiated β₁-adrenergic-induced Golgi Ca²+ release, which is consistent with compartmentalization of cAMP signaling near the Golgi apparatus. Interventions that stimulated Golgi Ca²+ release appeared to increase the trafficking of vascular endothelial growth factor receptor-1 (VEGFR-1) from the Golgi apparatus to the surface membrane of cardiomyocytes. In cardiomyocytes from rats with heart failure, decreases in the abundance of PDE3s and PDE4s were associated with increased Golgi Ca²+ release events. These data suggest that the Golgi apparatus is a focal point for β₁- adrenergicstimulated Ca²+ signaling and that the Golgi Ca²+ store functions independently from the sarcoplasmic reticulum and the global Ca²+ transients that trigger contraction in cardiomyocytes.