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Principles of Cell Signaling and Biological Consequences

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Student #14 Response

20 May 2005

14 14

This paper investigates the crosstalk between the Mu opioid receptor pathway and the insulin receptor pathway, which is an example of an interaction between GPCR and RTK pathwayw. The model is that the MOR pathway is a negative modulator of IR-mediated activation of the Act and ERK cascades. The activation of the MOR pathway caused the loss of IR- dependent phosphorylation of Act and ERK, and MOR activation was shown to disrupt the IRS-1/p85 PI3K and the IR/Shc/Grb2 complexes, which are needed for IR signal transduction. Finally, they demonstrate that treatment with morphine induces phosphorylation of IRS-1 in certain brain regions of wild -type mice, but this effect is abolished in MOR knockout mice. The combination of biochemical and mouse studies reinforces the authors' case; the experiments with MOR-knockout mice produced especially strong evidence of the in-vivo role of this crosstalk.

I feel that the results presented by the authors are convincing; I agree with the conclusions of this paper, and with Student #8's assessment thereof. I especially liked the fact that the authors mentioned the physiological background of their work, i.e. the role of opiods in glucose homeostasis. With the epidemic of Type II diabetes sweeping across our nation, any insights into the desensitization to insulin receptor signaling take on a high degree of medical importance. However, one of my concerns is that the biochemical work was done in cells overexpressing various signaling pathway components, which is a rather artificial system. It would have been a valuable additional experiment to use siRNA to knock out various pathway components in cells which express them endogenously. The only other issue is that I would have liked for the authors to include a diagram of their model. This would make the paper much more clear, especially since the authors propose that the MOR pathway disrupts the IRS-1/p85 PI3K and IR/Shc/Grb2 signaling complexes formed by the IR pathway, but not the IRS-1/Grb2 complex. Such complex interactions are best demonstrated with diagrams. Aside from this, I found this paper clear and well-presented.

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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882