Desensitization agonist-induced

Zhang L, Yunkai Y, Mackin S et al. Differential p opiate receptor phosphorylation and desensitization induced by agonists and phorbol esters. J Biol Chem 1996 271 11449-11454. 

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... 

Desensitization of the glycogenolytic response to H,-receptor stimulation has been observed following prolonged incubation of mouse cerebral cortical slices with histamine [250]. This is seen as a parallel shift of the concentration-response curve for histamine to higher agonist concentrations, with no significant change in the maximum response. The development of the desensitization induced by 10 pM histamine occurs with a half-time of 20 min and the respon-... 

Homologous desensitization is a form of desensitization which is mediated by agonist-induced activation of the same receptor. G-protein-coupled receptor kinases (GRKs) and arrestins are involved in this process, which leads to an uncoupling of the receptor from its G protein. 

The multiplicity of G proteins coupled to opiate receptors may explain how different opiates can bind to the same receptor yet induce different cellular responses. For example, morphine binds to the cloned rat fi receptor expressed in HEK 293, CHO and COS-7 cells and inhibits cAMP accumulation [80-82]. Morphine can be continuously applied to the cells for up to 16 h, and the potency and magnitude of morphine inhibition of adenylyl cyclase does not diminish [80, 81]. In contrast, the opiate sufentanil can bind to the same cloned fi receptor in HEK 293 cells to inhibit cAMP accumulation. However, sufentanil s actions rapidly desensitize [83]. Since both compounds bind to the same receptor, and the fi receptor is the only receptor these drugs can interact with in these cells, the ability of these two full agonists to differentially regulate the fi receptor must be due to their abilities to affect separate adaptive processes in these cells. 

While chronic morphine treatment uncouples the // receptor from K+ channels, it did not affect the coupling of ft receptors to adenylyl cyclase. Pretreatment of the cloned ft receptor expressed in HEK 293, AtT-20, CHO and COS cells with morphine or DAMGO for up to 16h did not alter the subsequent ability of fi agonists to inhibit cAMP accumulation [25, 65, 80-82]. These findings suggest that morphine treatment induces a selective desensitization of the coupling of the fi receptor to K+ channels. 

The carboxy terminus of the ft receptor was essential for agonist-induced desensitization [83, 132] since truncation of the receptor prevented desensitization. Like those findings with the k receptor, the enzyme G protein receptor kinase (GRK) appears to be involved in the desensitization process, since blockade of GRK prevented the desensitization process. Wang [132] has proposed that GRK catalyzes the phosphorylation of a series of serine/threonine residues in the C-terminus of the fi receptor to desensitize the receptor. 

Zimprich A, Simon T, Hollt V. Cloning and expression of an isoform of the rat mu opioid receptor (rMORIB) which differs in agonist induced desensitization from rMOR. FEBS Lett 1994 359 142-146... 

Kovoor A, Henry DJ, Chavkin C. Agonist-induced desensitization of the mu opioid receptor-coupled potassium channel (GIRK1). J Biol Chem 1995 270 589-595. 

If only a low level of receptor activation is required in order to obtain a full response, one would predict that receptor desensitization would be a smaller problem with THIP, muscimol, and other GABAa agonists used as hypnotics. In an animal study, Lancel and Langebartels showed that 5-d treatment with THIP produced sustained effects on sleep parameters, whereas a benzodiazepine in a similar paradigm induced tolerance-like effects after only 5 d of treatment (52). Accepting that only... 

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