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  • Title: Calcium channel upregulation in response to activation of neurotrophin and surrogate neurotrophin receptor tyrosine kinases.
    Author: Black MJ, Woo Y, Rane SG.
    Journal: J Neurosci Res; 2003 Oct 01; 74(1):23-36. PubMed ID: 13130503.
    Abstract:
    Modulation of calcium channel expression and function in the context of neurotrophin induced neuronal differentiation remains incompletely understood at a mechanistic level. We addressed this issue in the PC12 model neuronal system using patch clamp electrophysiology combined with ectopic expression of the human beta platelet-derived growth factor (betaPDGF) receptor as a surrogate neurotrophin receptor system. PC12 cells ectopically expressing the human betaPDGF receptor were treated with PDGF or nerve growth factor (NGF) for up to 7 days, and Ca2+ channel subtype expression was analyzed using selective pharmacological agents in both whole-cell and cell-attached single channel patch clamp configurations. PDGF-induced upregulation of N- and P/Q-type Ca2+ channel currents completely mimicked upregulation of these currents caused by NGF stimulation of the endogenous TrkA receptor tyrosine kinase (RTK). Neither PDGF nor NGF significantly altered L- or R-type currents. Single channel recordings together with immunocytochemistry implied that growth factor-induced increases in whole-cell Ca2+ currents were a result of synthesis of new channels, and that whereas increased N channel density was apparent in the soma, additional P/Q channels distributed preferentially to extrasomal locations, most likely the proximal neurites. Finally, specific signaling-deficient mutant forms of the betaPDGF receptor were used to show that activation of Src, PI3-kinase, RasGAP, PLCgamma or SHP-2 (some of which are implicated in certain other aspects of PC12 cell differentiation) by RTKs is not required for growth factor-induced Ca2+ channel upregulation. In contrast, activation of the Ras-related G-protein Rap1 was found critical to this process.
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