Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine Journal Article
| Authors: | Xu, J.; Lu, Z.; Narayan, A.; Le Rouzic, V. P.; Xu, M.; Hunkele, A.; Brown, T. G.; Hoefer, W. F.; Rossi, G. C.; Rice, R. C.; MartÃnez-Rivera, A.; Rajadhyaksha, A. M.; Cartegni, L.; Bassoni, D. L.; Pasternak, G. W.; Pan, Y. X. |
| Article Title: | Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine |
| Abstract: | Extensive 3? alternative splicing of the mu opioid receptor gene OPRM1 creates multiple C-terminal splice variants. However, their behavioral relevance remains unknown. The present study generated 3 mutant mouse models with truncated C termini in 2 different mouse strains, C57BL/6J (B6) and 129/SvEv (129). One mouse truncated all C termini downstream of Oprm1 exon 3 (mE3M mice), while the other two selectively truncated C-terminal tails encoded by either exon 4 (mE4M mice) or exon 7 (mE7M mice). Studies of these mice revealed divergent roles for the C termini in morphine-induced behaviors, highlighting the importance of C-terminal variants in complex morphine actions. In mE7M-B6 mice, the exon 7-associated truncation diminished morphine tolerance and reward without altering physical dependence, whereas the exon 4-associated truncation in mE4M-B6 mice facilitated morphine tolerance and reduced morphine dependence without affecting morphine reward. mE7M-B6 mutant mice lost morphine-induced receptor desensitization in the brain stem and hypothalamus, consistent with exon 7 involvement in morphine tolerance. In cell-based studies, exon 7-associated variants shifted the bias of several mu opioids toward ?-arrestin 2 over G protein activation compared with the exon 4-associated variant, suggesting an interaction of exon 7-associated C-terminal tails with ?-arrestin 2 in morphine-induced desensitization and tolerance. Together, the differential effects of C-terminal truncation illustrate the pharmacological importance of OPRM1 3? alternative splicing. |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 127 |
| Issue: | 4 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2017-04-01 |
| Start Page: | 1561 |
| End Page: | 1573 |
| Language: | English |
| DOI: | 10.1172/jci88760 |
| PROVIDER: | scopus |
| PUBMED: | 28319053 |
| PMCID: | PMC5373896 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 June 2017 -- Source: Scopus |
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