Threonine 180 Is Required for G-protein-coupled Receptor Kinase 3- and β-Arrestin 2-mediated Desensitization of the µ-Opioid Receptor in Xenopus Oocytes

To determine the sites in the µ-opioid receptor (MOR) critical for agonist-dependent desensitization, we constructed and coexpressed MORs lacking potential phosphorylation sites along with G-protein activated inwardly rectifying potassium channels composed of Kir3.1 and Kir3.4 subunits in Xenopus oocytes. Activation of MOR by the stable enkephalin analogue, [D-Ala2,MePhe4,Glyol5]enkephalin, led to homologous MOR desensitization in oocytes coexpressing both G-protein-coupled receptor kinase 3 (GRK3) and beta -arrestin 2 (arr3). Coexpression with either GRK3 or arr3 individually did not significantly enhance desensitization of responses evoked by wild type MOR activation. Mutation of serine or threonine residues to alanines in the putative third cytoplasmic loop and truncation of the C-terminal tail did not block GRK/arr3-mediated desensitization of MOR. Instead, alanine substitution of a single threonine in the second cytoplasmic loop to produce MOR(T180A) was sufficient to block homologous desensitization. The insensitivity of MOR(T180A) might have resulted either from a block of arrestin activation or arrestin binding to MOR. To distinguish between these alternatives, we expressed a dominant positive arrestin, arr2(R169E), that desensitizes G protein-coupled receptors in an agonist-dependent but phosphorylation-independent manner. arr2(R169E) produced robust desensitization of MOR and MOR(T180A) in the absence of GRK3 coexpression. These results demonstrate that the T180A mutation probably blocks GRK3- and arr3-mediated desensitization of MOR by preventing a critical agonist-dependent receptor phosphorylation and suggest a novel GRK3 site of regulation not yet described for other G-protein-coupled receptors

Dopamine D4 receptor counteracts morphine-induced changes in M opioid receptor signaling in the striosomes of the rat caudate putamen.

Morphine is one of the most potent analgesic drugs used to relieve moderate to severe pain. After long-term use of morphine, neuroadaptive changes in the brain promotes tolerance, which result in a reduced sensitivity to most of its effects with attenuation of analgesic efficacy, and dependence, revealed by drug craving and physical or psychological manifestations of drug withdrawal. The mu opioid receptor (MOR) is critical, not only in mediating morphine analgesia, but also in addictive behaviors by the induction of a strong rewarding effect. We have previously shown that dopamine D4 receptor (D4R) stimulation counteracts morphine-induced activation of dopaminergic nigrostriatal pathway and accumulation of Fos family transcription factors in the caudate putamen (CPu). In the present work, we have studied the effect of D4R activation on MOR changes induced by morphine in the rat CPu on a continuous drug treatment paradigm, by analyzing MOR protein level, pharmacological profile, and functional coupling to G proteins. Furthermore, using conditioned place preference and withdrawal syndrome test, we have investigated the role of D4R activation on morphine-related behavioural effects. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment. Interestingly, co-treatment of morphine with the dopamine D4 receptor (D4R) agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [3H]DAMGO Bmax values to the same degree as seen after continuous morphine treatment. In addition, the administration of the D4R agonist counteracts the rewarding effects of morphine, as well as the development of physical dependence. The present results give support for the existence of antagonistic functional D4R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine and preventing morphine-related behaviour.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Coherent Control of Magneto-optical Rotation in Inhomogeneously Broadened Medium

We extend our earlier investigations [Opt. Commun. {\bf 179}, 97 (2000)] on the enhancement of magneto-optical rotation (MOR) to include inhomogeneous broadening. We introduce a control field that counter-propagates with respect to the probe field. We derive analytical results for the susceptibilities corresponding to the two circular polarization components of the probe field. From the analytical results we identify and numerically demonstrate the region of parameters where significantly large magneto-optical rotation (MOR) can be obtained. From the numerical results we isolate the significance of the magnetic field and the control field in enhancement of MOR. The control field opens up many new regions of the frequencies of the probe where large magneto-optical rotation occurs. We also report that a large enhancement of MOR can be obtained by operating the probe and control field in two-photon resonance condition.Comment: REVTex format, 14 pages including 6 figures, to be published in Optics Communication

Smokeless tobacco - a substantial risk for oral potentially malignant disorders in South Asia

Data sources: Medline, the Science Citation Index (SCI) via Web of Science, Scopus, CINAHL, Global Index Medicus, Google Scholar and SLT-related reports of the International Agency for Research on Cancer and the National Cancer Institute of the United States. Study selection: Observational studies on the use of SLT and the risk of developing OPMDs in South Asian Populations. Data extraction and synthesis: Duplicate selection of studies was undertaken with two reviewers undertaking data abstraction and quality assessment independently. Risk and odds ratios were extracted or calculated for studies where possible. Meta odds ratios (mOR) were calculated using a random effects analysis. Results: Fifteen papers reporting 18 studies were included. The majority (12) were from India. All the studies were case-control designs. MOR for any OPMD with the use of any SLT product was 15.5 (95% CI; 9.9–24.2). Risk was higher in women; mOR = 22.2 (95% CI, 9.1–54.1) than men; mOR = 8.7 (95% CI, 2.1–34.8). Betel quid with tobacco carried the highest risk for OPMD, mOR = 16.1 (95% CI, 7.8–33.5). Conclusions: The findings of our study point towards a strong association between some forms of OPMDs and SLT use in South Asia. The risk estimates are high, irrespective of controlling for confounders such as smoking and alcohol or stratification by sex, country or source of controls. There is also an exposure-response relationship between OPMDs and SLT use

MOR Cryptosystem and classical Chevalley groups in odd characteristic

In this paper we study the MOR cryptosystem using finite classical Chevalley groups over a finite field of odd characteristic. In the process we develop an algorithm for these Chevalley groups in the same spirit as the row-column operation for special linear group. We focus our study on orthogonal and symplectic groups. We find the hardness of the proposed MOR cryptosystem for these groups