1Brain Res. 2011 Mar 1377: 32-40
TitlePotentiation of NGF-induced neurite outgrowth in PC12 cells by papaverine: role played by PLC-?, IP3 receptors.
AbstractPapaverine, an inhibitor of phosphodiesterase (PDE) 10A, is gaining attention for its potential in the treatment of neuropsychiatric diseases such as schizophrenia. However, the precise mechanisms underlying the putative neuroprotective/neurotrophic actions of papaverine remain unclear. Thus, we investigated the effects of papaverine on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Papaverine potentiated NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner. In contrast, the selective PDE10A inhibitor MP-10 had no effect on NGF-induced neurite outgrowth. The potentiation of NGF-induced neurite outgrowth by papaverine was blocked by the PLC-? inhibitor U73122. Furthermore, papaverine's potentiation of NGF-induced neurite outgrowth was also blocked by the co-administration of inositol 1,4,5-trisphosphate (IP(3)) receptor antagonists (xestospongin C and 2-aminoethoxydiphenyl borate (2-APB)) and by reduced expression of IP(3) receptor gene (i.e., ITPR1 and itpr3) by siRNA. Our findings suggest that papaverine could potentiate NGF-induced neurite outgrowth, and that activation of PLC-? and IP(3) receptors might be involved in the mechanism underlying papaverine's potentiation of neurite outgrowth in PC12 cells.
SCZ Keywordsschizophrenia
2Nat. Neurosci. 2015 May 18: 698-707
TitleDisrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a susceptibility gene for major psychiatric disorders, including schizophrenia. DISC1 has been implicated in neurodevelopment in relation to scaffolding signal complexes. Here we used proteomic analysis to screen for DISC1 interactors and identified several RNA-binding proteins, such as hematopoietic zinc finger (HZF), that act as components of RNA-transporting granules. HZF participates in the mRNA localization of inositol-1,4,5-trisphosphate receptor type 1 (ITPR1), which plays a key role in synaptic plasticity. DISC1 colocalizes with HZF and ITPR1 mRNA in hippocampal dendrites and directly associates with neuronal mRNAs, including ITPR1 mRNA. The binding potential of DISC1 for ITPR1 mRNA is facilitated by HZF. Studies of Disc1-knockout mice have revealed that DISC1 regulates the dendritic transport of ITPR1 mRNA by directly interacting with its mRNA. The DISC1-mediated mRNA regulation is involved in synaptic plasticity. We show that DISC1 binds ITPR1 mRNA with HZF, thereby regulating its dendritic transport for synaptic plasticity.
SCZ Keywordsschizophrenia