Abstract:
:The G protein-coupled muscarinic acetylcholine receptor (mAChR) isoforms have been identified in neural stem/progenitor (or precursor) cells. In previous studies, activation of these receptors induced elevations in intracellular Ca(2+) signals and mitogen-activated protein (MAP) kinase activity that led to enhanced DNA synthesis along with neurogenesis in neural precursor cells. Here we report that the nonreceptor protein tyrosine kinase c-src activity is required for the muscarinic receptor-activated MAP kinase and cAMP-responsive element-binding protein (CREB). Stimulation of neural precursor cells dissociated from embryonic day 13 rat cortical neuroepithelium with the muscarinic receptor agonist carbachol (CCh) induced phosphorylations of c-src that were detected by antibodies raised against phospho-Tyr416 (Ptyr416), phospho-Tyr527 (Ptyr527), and phospho-Tyr215 (Ptyr215) of the kinase. Although an increase in Ptyr416 suggested direct activation of c-src, Ptyr215 may serve as an alternative mechanism underlying activation of c-src without dephosphorylation of Ptyr-527. Both extracellular signal-regulated kinase (Erk1/2) and CREB were significantly activated after CCh treatment indicated by increases in phosphorylation of these two proteins. The c-Src inhibitor PP1 abolished the CCh-induced activation of Erk1/2 and CREB in a dose-dependent manner. Moreover, CCh stimulated expression of the neuronal specific marker MAP2, which was inhibited by PP1. Cell proliferation assays and immunocytochemistry revealed that PP1 inhibited the CCh-induced DNA synthesis and MAP2(+) production. These results suggest that c-src activity is essential for the muscarinic receptor-mediated proliferation and neurogenesis in neural precursor cells via Erk1/2 and CREB signaling pathways.
journal_name
J Neurosci Resjournal_title
Journal of neuroscience researchauthors
Zhao WQ,Alkon DL,Ma Wdoi
10.1002/jnr.10591keywords:
subject
Has Abstractpub_date
2003-05-01 00:00:00pages
334-42issue
3eissn
0360-4012issn
1097-4547journal_volume
72pub_type
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