Abstract
Neurodegeneration occurs due to neuronal cell death and subsequently disrupts neuronal networks. In current medicine, methods for interruption of neuronal cell death and avoidance of disruption of neuronal networks have potential as therapy for neurodegenerative disorders. Development of this therapy requires analysis of the molecular mechanism of neurite extension that leads to network formation. Here, we show that forskolin (fsk), an activator of adenylate cyclase, increases the intracellular cAMP concentration and induces neurite outgrowth in PC12 cells. The effect of fsk on neurite outgrowth was diminished by H89, an inhibitor of protein kinase A (PKA), and by PD98059 and U0126, which are inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway. With fsk treatment in the presence of tunicamycin, an inducer of cell death, the activity of the glucose-regulated protein 78 (GRP78) promoters was upregulated. Interestingly, this effect was completely abolished by H89 and by PD98059 and U0126. This phenomenon was confirmed using a dominant-negative PKA-expressing PC12 cell line, in which the PKA-mediated signaling pathway was completely eliminated. These lines of evidence suggest that GRP78 promotes neuronal elongation that is regulated by fsk and mediated by PKA.
Highlights
Materials and MethodsThe endoplasmic reticulum (ER) is an important organelle with a crucial role in protein biosynthesis
We found that Glucose-regulated protein 78 (GRP78) expression is regulated via protein kinase A (PKA)-mediated signaling
Neurite outgrowth was markedly induced by forskolin, an activator of adenylate cyclase, which activates PKAmediated signaling
Summary
Materials and MethodsThe endoplasmic reticulum (ER) is an important organelle with a crucial role in protein biosynthesis. OASIS is a sensor of unfolded proteins that upregulates GRP78 expression, but this effect is limited only to glial cells [13]. We show that forskolin (fsk), an activator of adenylate cyclase, attenuates Tm-mediated cell death and promotes elongation of neurites in pheochromocytoma 12 (PC12) cells. We discover that fsk-mediated PKA signaling upregulates GRP78 to bear neurites via an effect on the GRP78 promoter region by using PC12 cells.
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