Differential expression of the alternatively spliced OPRM1 isoform μ-opioid receptor-1K in HIV-infected individuals

Abstract

Objective We previously examined the expression of specific C-terminal μ-opioid receptor (MOR) splice variants in human central nervous system cell types and HIV-infected brain tissue from subjects with neurocognitive impairment ± HIV encephalitis (HIVE). In the present study, we examined the N-terminal splice variant MOR-1K which mediates excitatory cellular signaling. Methods and Results We found segregation of expression ranging from undetectable to seemingly exclusive across nervous system cell types compared to the pool of C-terminal MOR splice variants using RT-PCR. Expression of MOR-1K mRNA was also increased in HIV-infected subjects with combined neurocognitive impairment and HIVE compared to the other groups. MOR-1K expression correlated with the level of subject neurocognitive impairment whereas the pool of C-terminal MOR splice variants did not. HIVE was also associated with increased expression of the inflammatory mediators MCP-1, MCP-2, and RANTES, but not the host HIV co-receptors CXCR4 and CCR5 or the CD4 receptor, using qRT-PCR. Network analysis of microarray data from these same subjects revealed filamin A (FLNA) as a possible interaction partner with MOR-1K, and FLNA gene expression was also found to be upregulated in HIVE using qRT-PCR. Overexpression of filamin A in HEK293 cells redistributed MOR-1K from intracellular compartments to the cell surface. Conclusion These results suggest that HIVE, and neurocognitive impairment depending on its severity, are associated with enhanced MOR-1K signaling through both increased expression and trafficking to the cell surface, which may alter the contribution of MOR receptor isoforms and exacerbate the effects of MOR activation in neuroAIDS.

Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

“…The importance of 6-TM variants was further supported by recent studies showing the rescue of IBNtxA analgesia in knockout mice lacking 6-TM variants that were insensitive to IBNtxA by the lentiviral-mediated delivery of a 6-TM variant, mMOR-1G. It was reported that mMOR-1K, which exhibited excitatory cellular signaling, was elevated in HIV-infected individuals with combined neurocognitive impairment (NCI) and HIV encephalitis (HIVE) in relation to β-Adrenergic receptor and the inflammatory mediators MCP-1, MCP-2, and RANTES [62,63]. In addition, the 129S6 mice exhibited an analgesic response correlating to a measured decrease in MOR-1K gene expression levels, while CXB7/ByJ mice exhibited a hyperalgesic response correlating to a measured increase in MOR-1K gene expression levels, revealing that mMOR-1K contributes to the development of opioid-induced hyperalgesia [64].…”

Interactions of HIV and Drugs of Abuse

“…Moreover, selective MOR agonists such as endomorphin-1, but not DAMGO or morphine (Peterson et al, 1999) can increase HIV-1 replication in infected microglia—suggesting the involvement of a non-traditional MOR variant in HIV replication (Peterson et al, 1999) or suggesting that “biased agonism” (Hauser et al, 2012) may be operative. We have recently found that specific subsets of MOR splice variants, including MOR-1X and MOR-1K were differentially expressed by human astrocytes, but not expressed at detectable levels in microglia (Dever, Xu, Fitting, Knapp, & Hauser, 2012; Dever et al, 2014). Moreover, the expression of each MOR variant may be differentially regulated by HIV and in a cell specific manner (Dever et al, 2012; Dever et al, 2014).…”

“…We have recently found that specific subsets of MOR splice variants, including MOR-1X and MOR-1K were differentially expressed by human astrocytes, but not expressed at detectable levels in microglia (Dever, Xu, Fitting, Knapp, & Hauser, 2012; Dever et al, 2014). Moreover, the expression of each MOR variant may be differentially regulated by HIV and in a cell specific manner (Dever et al, 2012; Dever et al, 2014). Thus, microglia express a subset of MOR variants each of which may respond uniquely to morphine and/or HIV (Dever et al, 2012; Dever et al, 2014).…”

Bivalent Ligands Targeting Chemokine Receptor Dimerization: Molecular Design and Functional Studies

“…The MOR undergoes extensive alternative splicing and these splice variants may lead to cell-specific effects and unique pharmacological profiles [78–80]. Increasing evidence has shown that MOR splice variants could directly affect HIV infection, susceptibility, and progression [78,79].…”

“…The MOR undergoes extensive alternative splicing and these splice variants may lead to cell-specific effects and unique pharmacological profiles [78–80]. Increasing evidence has shown that MOR splice variants could directly affect HIV infection, susceptibility, and progression [78,79]. When comparing the expression rates of three different MOR splice variants (MOR-1, MOR-1A, and MOR-1X), Dever et al found that they were differentially expressed in the individual CNS cell types [79].…”