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

TitleDifferential expression of the alternatively spliced OPRM1 isoform μ-opioid receptor-1K in HIV-infected individuals.
Publication TypeJournal Article
Year of Publication2014
AuthorsDever, SM, Costin, BN, Xu, R, El-Hage, N, Balinang, J, Samoshkin, A, O'Brien, MA, McRae, M, Diatchenko, L, Knapp, PE, Hauser, KF
JournalAIDS
Volume28
Issue1
Pagination19-30
Date Published2014 Jan 2
ISSN1473-5571
KeywordsAIDS Dementia Complex, HIV Infections, Humans, Protein Isoforms, Real-Time Polymerase Chain Reaction, Receptors, Opioid, mu, RNA Splicing
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 individuals 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 the real-time polymerase chain reaction (RT-PCR). Expression of MOR-1K mRNA was also increased in HIV-infected individuals with combined neurocognitive impairment and HIVE compared with the other groups. MOR-1K expression correlated with the level of patient 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 coreceptors CXCR4 and CCR5 or the CD4 receptor using qRT-PCR. Network analysis of microarray data from these same patients 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 FLNA 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.

DOI10.1097/QAD.0000000000000113
Alternate JournalAIDS
PubMed ID24413261
PubMed Central IDPMC3939043
Grant List5R41 DA032293-02 / DA / NIDA NIH HHS / United States
5T90 DE021986-02 / DE / NIDCR NIH HHS / United States
5U01 MH083500 / MH / NIMH NIH HHS / United States
F32 DA033898 / DA / NIDA NIH HHS / United States
F32 DA033898 / DA / NIDA NIH HHS / United States
K02 DA027374 / DA / NIDA NIH HHS / United States
K02 DA027374 / DA / NIDA NIH HHS / United States
N01 MH32002 / MH / NIMH NIH HHS / United States
NS38841 / NS / NINDS NIH HHS / United States
R01 DA018633 / DA / NIDA NIH HHS / United States
R01 DA018633 / DA / NIDA NIH HHS / United States
R01 DA024461 / DA / NIDA NIH HHS / United States
R01 DA024461 / DA / NIDA NIH HHS / United States
R01 DA033200 / DA / NIDA NIH HHS / United States
R01 DA034231 / DA / NIDA NIH HHS / United States
R01 DA034231 / DA / NIDA NIH HHS / United States
R24 MH59724 / MH / NIMH NIH HHS / United States
R24 MH59745 / MH / NIMH NIH HHS / United States
R24 NS45491 / NS / NINDS NIH HHS / United States
R41 DA032293 / DA / NIDA NIH HHS / United States
T32 DA007027 / DA / NIDA NIH HHS / United States
T32 DA007027 / DA / NIDA NIH HHS / United States
T90 DE021986 / DE / NIDCR NIH HHS / United States
U01 MH083500 / MH / NIMH NIH HHS / United States
U01 MH083501 / MH / NIMH NIH HHS / United States
U01 MH083501 / MH / NIMH NIH HHS / United States
U01 MH083506 / MH / NIMH NIH HHS / United States
U01 MH083506 / MH / NIMH NIH HHS / United States
U01 MH083507 / MH / NIMH NIH HHS / United States
U01 MH083507 / MH / NIMH NIH HHS / United States
U01 MH083545 / MH / NIMH NIH HHS / United States
U01 MH083545 / MH / NIMH NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States
U24 MH100929 / MH / NIMH NIH HHS / United States
U24 MH100931 / MH / NIMH NIH HHS / United States