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Inhibition of insulin-like growth factor-I signaling by ethanol in neuronal cells
H Hallak1, A E Seiler, J S Green
1Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Background:
Ethanol inhibits insulin-like growth factor-I receptor (IGF-IR) activation. However, the potency of ethanol for inhibition of the IGF-IR and other receptor tyrosine kinases varies considerably among different cell types. We investigated the effect of ethanol on IGF-I signaling in several neuronal cell types.
Methods:
IGF-I signaling was examined in SH-SY5Y neuroblastoma cells, primary cultured rat cerebellar granule neurons, and rat NG-108 neuroblastoma x glioma hybrids. The tyrosine phosphorylation of IGF-IR, IRS-2, Shc, and p42/p44 MAP kinase (MAPK), and the association of Grb-2 with Shc, were examined by immunoprecipitations and Western blotting.
Results:
IGF-I-mediated tyrosine phosphorylation of MAPK was inhibited by ethanol in all cell lines. IGF-IR autophosphorylation was markedly inhibited by ethanol in SH-SY5Y cells, was only mildly inhibited in cerebellar granule neurons, and was unaffected in rat NG-108 cells. In vitro tyrosine autophosphorylation of immunopurified IGF-IR obtained from all cell lines was inhibited by ethanol. There was also differential ethanol sensitivity of IRS-2 and Shc phosphorylation, and the association of Shc with IRS-2, among the different cell types.
Conclusions:
The findings demonstrate that IGF-I-mediated MAPK activation is a sensitive target of ethanol in diverse neuronal cell types. The data are consistent with ethanol-induced inhibition of IGF-IR activity, although the extent of IGF-IR tyrosine autophosphorylation per se is a poor marker of the inhibitory action of ethanol on this receptor. Furthermore, despite uniform inhibition of MAPK in the different neuronal cell types, tyrosine phosphorylation of proximal mediators of the IGF-IR are differentially inhibited by ethanol.
Insights
Ethanol inhibits insulin-like growth factor-I receptor (IGF-IR) signaling and downstream MAP kinase activation in neuronal cells. However, ethanol
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Ethanol is known to inhibit insulin-like growth factor-I receptor (IGF-IR) activation.
- The inhibitory effect of ethanol on IGF-IR and other receptor tyrosine kinases varies across cell types.
- Investigated ethanol's impact on IGF-I signaling in various neuronal cell types.
Purpose of the Study:
- To investigate the effect of ethanol on IGF-I signaling pathways in different neuronal cell types.
- To determine the differential sensitivity of neuronal cells to ethanol-induced inhibition of IGF-I signaling.
- To elucidate the mechanisms underlying ethanol's effects on IGF-IR and its downstream effectors.
Main Methods:
- Utilized SH-SY5Y neuroblastoma cells, primary rat cerebellar granule neurons, and NG-108 neuroblastoma x glioma hybrid cells.
- Examined tyrosine phosphorylation of IGF-IR, IRS-2, Shc, and p42/p44 MAP kinase (MAPK) using immunoprecipitation and Western blotting.
- Assessed the association of Grb-2 with Shc.
Main Results:
- Ethanol inhibited IGF-I-mediated MAPK phosphorylation in all tested neuronal cell lines.
- Ethanol markedly inhibited IGF-IR autophosphorylation in SH-SY5Y cells, mildly in cerebellar neurons, and not at all in NG-108 cells.
- In vitro studies showed ethanol inhibited tyrosine autophosphorylation of immunopurified IGF-IR from all cell types, indicating differential sensitivity of proximal signaling mediators.
Conclusions:
- IGF-I-mediated MAPK activation is a sensitive target for ethanol inhibition in diverse neuronal cells.
- Ethanol inhibits IGF-IR activity, but IGF-IR tyrosine autophosphorylation is an unreliable marker for this inhibition.
- Despite uniform MAPK inhibition, proximal IGF-IR signaling components exhibit differential ethanol sensitivity across neuronal cell types.
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