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Differential expression and HIV-1 regulation of μ-opioid receptor splice variants across human central nervous system cell types

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Abstract

The μ-opioid receptor (MOR) is known to undergo extensive alternative splicing as numerous splice variants of MOR have been identified. However, the functional significance of MOR variants, as well as how splice variants other than MOR-1 might differentially regulate human immunodeficiency virus type-1 (HIV-1) pathogenesis in the central nervous system (CNS), or elsewhere, has largely been ignored. Our findings suggest that there are specific differences in the MOR variant expression profile among CNS cell types, and that the expression levels of these variants are differentially regulated by HIV-1. While MOR-1A mRNA was detected in astroglia, microglia, and neurons, MOR-1 and MOR-1X were only found in astroglia. Expression of the various forms of MOR along with the chimeric G protein qi5 in HEK-293T cells resulted in differences in calcium/NFAT signaling with morphine treatment, suggesting that MOR variant expression might underlie functional differences in MOR-effector coupling and intracellular signaling across different cell types. Furthermore, the data suggest that the expression of MOR-1 and other MOR variants may also be differentially regulated in the brains of HIV-infected subjects with varying levels of neurocognitive impairment. Overall, the results reveal an unexpected finding that MOR-1 may not be the predominant form of MOR expressed by some CNS cell types and that other splice variants of MOR-1, with possible differing functions, may contribute to the diversity of MOR-related processes in the CNS.

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Acknowledgments

We thank Michael F. Miles for providing us with the SHSY-5Y cells. MOR-1 and MOR-1X plasmid cDNAs were kind gifts of Gavril W. Pasternak, and MOR-1A plasmid cDNA was a kind gift from Raymond L. White. We are also most grateful to the subjects who provided samples that were analyzed in this study. We gratefully acknowledge the support of the National Institutes of Health (NIH)-National Institute on Drug Abuse grants T32 DA007027, R01 DA024461, R01 DA018633, and K02 DA027374. The human tissue provided by the National NeuroAIDS Tissue Consortium (NNTC) for this publication was made possible from NIH funding through the National Institute of Mental Health and National Institute of Neurological Disorders and Stroke by the following grants: Manhattan HIV Brain Bank: U01MH083501, R24MH59724; Texas NeuroAIDS Research Center: U01MH083507, R24NS45491; National Neurological AIDS Bank: 5U01MH083500, NS38841; California NeuroAIDS Tissue Network: U01MH083506, R24MH59745; and Statistics and Data Coordinating Center: U01MH083545, N01MH32002. This publication's contents are solely the responsibility of the authors and do not necessarily represent the official view of the NNTC or the NIH.

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Correspondence to Seth M. Dever.

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Seth M. Dever and Ruqiang Xu contributed equally to this work.

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Dever, S.M., Xu, R., Fitting, S. et al. Differential expression and HIV-1 regulation of μ-opioid receptor splice variants across human central nervous system cell types. J. Neurovirol. 18, 181–190 (2012). https://doi.org/10.1007/s13365-012-0096-z

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  • DOI: https://doi.org/10.1007/s13365-012-0096-z

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