التفاصيل البيبلوغرافية
| العنوان: |
Muscarinic receptor antagonists activate ERK-CREB signaling to augment neurite outgrowth of adult sensory neurons. |
| المؤلفون: |
Sabbir, Mohammad Golam1 msabbir@sbrc.ca, Fernyhough, Paul1,2 PFernyhough@sbrc.ca |
| المصدر: |
Neuropharmacology. Dec2018, Vol. 143, p268-281. 14p. |
| مصطلحات موضوعية: |
*NEURONS, *EXTRACELLULAR signal-regulated kinases |
| مستخلص: |
Abstract A major cellular effector activated by G protein coupled receptors is extracellular signal-regulated kinase (ERK). The ERK signaling cascade regulates a variety of cellular processes including growth and proliferation. Both G protein and β-arrestin-mediated signaling lead to ERK activation by phosphorylation through different kinases. Recently, we have shown muscarinic acetylcholine type 1 receptor (M 1 R) antagonists, muscarinic toxin 7 (MT7) and pirenzepine, elevated neurite outgrowth and protected from small and large fiber neuropathy in adult sensory neurons in various animal models. Thus, we tested the novel hypothesis that muscarinic antagonists could drive neurite outgrowth through altered M 1 R-ERK signaling. We have used two dimensional isoelectric focusing/SDS-PAGE combined with analysis using multiple phospho-epitope specific antibodies to study ERK1/2 phosphorylation and activation of its downstream nuclear effector cyclic response element binding protein (CREB). Activated CREB is known to exhibit neuroprotective and growth promoting effects. One hour of treatment with MT7 and pirenzepine activated ERK through M 1 R and induced a significant increase in levels of pCREB(S133) in cultured sensory neurons. Further, pharmacological blockade or siRNA based knockdown of ERK abolished the MT7 and pirenzepine mediated neuritogenic effect. In addition, we have shown drug-induced alterations of charged protein fractions that may possess additional post-translationally modified forms of ERK and CREB. For the first time we show that long-term treatment, e.g. 1 h, with muscarinic antagonists selective or specific for M 1 R can activate a biased β-arrestin dependent ERK-CREB signal cascade. Our study gives novel insight into muscarinic antagonist-mediated modulation of M 1 R-ERK-CREB signaling which could be exploited for therapy in neuropathic diseases. Graphical abstract Image 1 Highlights • M 1 R antagonists, MT7 and pirenzepine, activate ERK-CREB signaling. • Antagonist-M 1 R interaction induced sustained ERK signaling at 1 h of drug interaction. • MT7 and pirenzepine exhibited β-arrestin dependent biased ERK signaling. • Novel demonstration of biased GPCR signaling by muscarinic antagonists. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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