更新于：2024-11-01

FLNA x μ opioid receptor

更新于：2024-11-01

基本信息

关联

项与 FLNA x μ opioid receptor 相关的药物

PTI-609

靶点

FLNA x μ opioid receptor

作用机制

FLNA modulators [+1]

在研机构-

原研机构

Cassava Sciences, Inc.

在研适应症-

非在研适应症

炎症 [+1]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 FLNA x μ opioid receptor 相关的临床结果

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100 项与 FLNA x μ opioid receptor 相关的转化医学

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0 项与 FLNA x μ opioid receptor 相关的专利（医药）

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项与 FLNA x μ opioid receptor 相关的文献（医药）

2014-01-02·AIDS2区 · 医学

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

2区 · 医学

Article

作者: Samoshkin, Alexander ; Knapp, Pamela E. ; Dever, Seth M. ; El-Hage, Nazira ; Costin, Blair N. ; McRae, MaryPeace ; Xu, Ruqiang ; Balinang, Joyce ; Diatchenko, Luda ; Hauser, Kurt F. ; O'Brien, Megan A.

OBJECTIVEWe 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 RESULTSWe 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.CONCLUSIONThese 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.

2012-03-01·Molecular and Cellular Biology3区 · 生物学

A Switch of G Protein-Coupled Receptor Binding Preference from Phosphoinositide 3-Kinase (PI3K)–p85 to Filamin A Negatively Controls the PI3K Pathway

3区 · 生物学

Article

作者: Estève, Jean-Pierre ; Fourmy, Daniel ; Mollereau, Catherine ; Schulz, Stefan ; Lättig, Jens ; Susini, Christiane ; Saint-Laurent, Nathalie ; Bousquet, Corinne ; Pyronnet, Stéphane ; Boutet-Robinet, Elisa ; Najib, Souad

ABSTRACTFrequent oncogenic alterations occur in the phosphoinositide 3-kinase (PI3K) pathway, urging identification of novel negative controls. We previously reported an original mechanism for restraining PI3K activity, controlled by the somatostatin G protein-coupled receptor (GPCR) sst2 and involving a ligand-regulated interaction between sst2 with the PI3K regulatory p85 subunit. We here identify the scaffolding protein filamin A (FLNA) as a critical player regulating the dynamic of this complex. A preexisting sst2-p85 complex, which was shown to account for a significant basal PI3K activity in the absence of ligand, is disrupted upon sst2 activation. FLNA was here identified as a competitor of p85 for direct binding to two juxtaposed sites on sst2. Switching of GPCR binding preference from p85 toward FLNA is determined by changes in the tyrosine phosphorylation of p85- and FLNA-binding sites on sst2 upon activation. It results in the disruption of the sst2-p85 complex and the subsequent inhibition of PI3K. Knocking down FLNA expression, or abrogating FLNA recruitment to sst2, reversed the inhibition of PI3K and of tumor growth induced by sst2. Importantly, we report that this FLNA inhibitory control on PI3K can be generalized to another GPCR, the mu opioid receptor, thereby providing an unprecedented mechanism underlying GPCR-negative control on PI3K.

2010-12-01·Neurochemical Research3区 · 医学

The Interaction Between the Mu Opioid Receptor and Filamin A

3区 · 医学

Article

作者: Irma Onoprishvili ; Eric J. Simon

Our laboratory embarked on research to discover proteins the interaction of which with the mu opioid receptor (MOPr) is required for its function and regulation. We performed yeast two-hybrid screens, using the carboxy tail of the human MOPr as bait and a human brain library. This yielded a number of proteins that seemed to bind to the MOPr C-tail. The one we chose to study in detail was filamin A (FLNA). Evidence was obtained that there was indeed protein-protein binding between the C-tail of MOPr and FLNA. A human melanoma cell line (M2) lacking the gene for FLNA and a control cell line (A7) which differed from M2 only in having been transfected with the gene for FLNA and expressing the FLNA protein were made available to us. We transfected these cell lines with the gene for MOPr and used them in our studies. The absence of FLNA strongly reduced MOPr downregulation as well as desensitization of adenylyl cyclase inhibition and G protein activation. A recent finding, published here for the first time, is that FLNA is required for the activation by mu opioid agonists of the MAP kinase p38. Deletion studies indicated that the MOPr binding site on FLNA is in the 24th repeat, close to its C-terminal. It was further found that FLNA lacking the N-terminal actin binding domain is as capable as full length FLNA to restore cells to control status, suggesting that actin binding is not required. A surprising finding was that upregulation of MOPr by morphine and some agonist analogs occurs in M2 cells lacking FLNA, whereas normal receptor downregulation takes place in A7 cells.