Endocytosis resensitization

Beyer, A., Koch, T., Schroder, H., Schulz, S and HoUt, V. (2004) Effect of the Al 18G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. J. Neurochem. 89, 553-560. 

Gray JA, Sheffler DJ, Bhatnagar A, et al. Cell-type specific effects of endocytosis inhibitors on 5-hydroxytryptamine(2A) receptor desensitization and resensitization reveal an arrestin-, GRK2-, and GRK5-independent mode of regulation in human embryonic kidney 293 cells. Mol Pharmacol 2001 60 1020-1030. 

However, it is clear that opioid receptor endocytosis is critical for the receptor to resensitize. Wolf et al. [170] reported the mutation of Thr394 of mu opioid receptor to Ala resulted in the rapid internalization and resensitization of receptor. Similar observations were reported with various spliced variants of mu opioid receptor, in which the rate of desensitization appears to correlate inversely with the resensitization properties of receptor [169]. Such observations and others have led to a hypothesis proposed by Whistler et al. [140] that the ability of various opioid agonists to produce tolerance is dependent on their RAVE values. In their hypothesis, agonist that induces rapid receptor internalization, e.g., etorphine, would develop less tolerance in animals than agonist such as morphine, which does not produce receptor... 

Here we provide the basic methods we use to study chemokine-receptor trafficking. These methods have been used in conjunction with chemokines and chemokine antagonists, and with other agents (e.g., phorbol esters) that can induce receptor endocytosis. In the following protocols, we refer only to the use of chemokines. We use the operational terms endocytosis and recycling to avoid alternative expressions such as down-modulation or down-regulation, desensitization, and resensitization, which may be used to reflect the functional state of the receptor or cell. 

Oakley, R.H., Laporte, S.A., Holt, J.A., Barak, L.S., Caron, M.G. (1999). Association of beta-arrestin with G protein-coupled receptors during clathrin-mediated endocytosis dictates the profile of receptor resensitization. J. 5io/. Chem. 274 32248-57. 

Internalization or sequestration of receptors away from the cell surface also occurs more slowly (minutes to hours) than desensitization. Although it might be facilitated by receptor phosphorylation, it can also occur in the absence of phosphorylation. In many instances, internalization is dependent on an interaction with arrestin molecules, which then target receptors for endocytosis via clathrin-coated pits. Once internalized, receptors are either recycled to the cell surface (resensitization) or are degraded in lysosomes. 

Activation of chemokine receptors ultimately results in desensitization, which has been associated with phosphorylation of serines and threonines in the C tail, and clathrin-mediated endocytosis (Ali et al., 1999 Oppermann et al., 1999 Yang et al., 1999). This process may be important for receptor resensitization and chemotaxis. Signaling is not required for HIY... 

Yang, W., Wang, D., and Richmond, A. (1999). Role of clathrin-mediated endocytosis in CXCR2 sequestration, resensitization, and signal transduction. J. Biol. Chem. 274, 11328-11333. 

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