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Principles of Cell Signaling and Biological Consequences

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Final Forum: Student #4

10 May 2005

Anonymous

Selected Publication:

Li Y, Eitan S, Wu J, Evans CJ, Kieffer B, Sun X, Polakiewicz RD. 2003. Morphine induces desensitization of insulin receptor signaling. Mol Cell Biol. 23(17): 6255-6266

There is increasing evidence that a number of G-protein coupled receptors (GPCRs) functionally interact with receptor tyrosine kinases (RTKs). The notion that such cross-talk could occur between the mu-opioid receptor (MOR) and the insulin receptor (IR) stemmed from earlier observations that centrally administered morphine resulted in hyperglycemic effects (Feldberg & Gupta, 1974), and that insulin increased the intrinsic efficacy of MOR agonists in Xenopus oocytes (McLaughlin et al., 2001). The MOR and the IR activate similar signaling pathways, including the Akt and ERK pathways. Previous studies by Polakiewicz et al. (1998) established a functional role for MOR-induced ERK activation in a feedback signal required for MOR desensitization. The findings in the present paper by Li et al. (2003) indicate that MOR-induced ERK activation can also play a functional role in modulating downstream IR signaling pathways.

In cells expressing endogenous or transfected MOR, IR, and insulin receptor substrate IRS-1, morphine pretreatment completely abolished insulin-induced phosphorylation of Akt and ERK in a receptor-specific and ERK-dependent manner. The effects of morphine on serine/threonine phosphorylation of the IR and IRS-1 were investigated, since such phosphorylation events attenuate insulin signaling and have been implicated in insulin resistance (Zick, 2001). As predicted, morphine induced serine phosphorylation of the IR and IRS-1, in an ERK-dependent manner. The effect of morphine on the integrity of IR/IRS-1/effector complexes was then examined. Morphine attenuated the insulin- mediated tyrosine phosphorylation of the adaptor protein Shc, impairing the formation of an active complex among the IR, Shc, and Grb2. This could explain the mechanism for morphine- induced attenuation of IR signaling to ERK, as Shc normally interacts with Grb2 to relay the insulin signal to the Ras/ERK cascade. Furthermore, morphine disrupted the interaction between IRS-1 and the p85 subunit of phosphatidylinositol 3-kinase (PI3K) by reducing tyrosine phosphorylation of IRS-1 at its p85 binding site. This could explain the mechanism for morphine-induced attenuation of IR signaling to Akt, since PI3K activation leads to stimulation of Akt. Thus, MOR activation of the ERK cascade appears to attenuate IR signaling to Akt and ERK by disrupting the integrity of two different signaling complexes. Finally, acute morphine administration increased IRS-1 serine phosphorylation in discrete brain regions of wild-type but not MOR knockout mice, illustrating the receptor specificity and physiological relevance of these findings.

Overall, this paper convincingly demonstrates the functional cross- talk between the MOR and the IR. A series of well-designed experiments were performed in both heterologous cell lines and native expression systems, using a combination of pharmacological, biochemical, and genetic tools to provide direct evidence for unidirectional cross-talk between MOR and IR signaling pathways. The importance of signaling complexes in signal transduction was also illustrated, as the disruption of these complexes by an independent signaling cascade can completely alter the outcome of the signaling pathway.

The cross-talk between the MOR and the IR could explain morphine-induced insulin resistance. As this has not been explicitly established, however, it will be necessary to further explore the direct interactions between morphine and insulin signaling systems to determine whether the hyperglycemic effects of morphine can truly be explained by cross-talk.

References:

Feldberg W & Gupta KP. 1974. Morphine hyperglycemia. J Physiol. 238: 487-502 [PubMed]

McLaughlin JP & Chavkin C. 2001. Tyrosine phosphorylation of the mu-opioid receptor regulates agonist intrinsic efficacy. Mol Pharmacol. 59: 1360-1368 [PubMed] [Online Journal]

Polakiewicz RD et al. 1998. A mitogen-activated protein kinase pathway is required for mu-opioid receptor desensitization. J Biol Chem. 273: 12402-12406 [PubMed] [Online Journal]

Zick Y. 2001. Insulin resistance: a phosphorylation-based uncoupling of insulin signaling. Trends Cell Biol. 11: 437-441 [PubMed] [Online Journal]

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