TargetRx Atlas

MRNA basic information

  • mRNA ID:ENST00000372330
  • Gene Name:MMP9
  • mRNA database:Ensembl
  • mRNA expression :up-regulated
  • mRNA Method:RT-PCR
  • mRNA Pathway:NA
  • Evidence:validated
  • (mRNA-drug)

Drug basic information

  • Drug ID:DB05381
  • Drug Name:Histamine
  • Drug Method:up-regulated the gene expression

Disease basic infommation

  • Disease:alzheimer＇s disease
  • Tissue:cell line U373

Other information

  • Title:Histamine induces the production of matrix metalloproteinase-9 in human astrocytic cultures via H1-receptor subtype
  • Journal:Brain Structure & Function
  • Published:2016
  • PubMed ID:25682263
  • Abstract:Accumulation of β-amyloid (Aβ) protein within the brain is a neuropathological hallmark of Alzheimer＇s disease (AD). One strategy to facilitate Aβ clearance from the brain is to promote Aβ catabolism. Matrix metalloproteinase-9 (MMP-9), a member of the family of Zn(+2)-containing endoproteases, known to be expressed and secreted by astrocytes, is capable of degrading Aβ. Histamine, a major aminergic brain neurotransmitter, stimulates the production of MMP-9 in keratinocytes through the histamine H1 receptor (H1R). In the present study, we show that histamine evokes a concentration- and calcium-dependent release of MMP-9 from human astrocytic U373 cells and primary cultures of human and rat astrocytes through the H1R subtype. Activation of H1R on astrocytes elevated intracellular levels of Ca(2+) that was accompanied by time-dependent increases in MAP kinase p44/p42 and PKC. In-cell western blots revealed dose-dependent increases in both enzymes, confirming involvement of these signal transduction pathways. We next investigated the extent of recombinant human MMP-9 (rhMMP-9) proteolytic activity on soluble oligomeric Aβ (soAβ). Mass spectrometry demonstrated time-dependent cleavage of soAβ (20 μM), but not another amyloidogenic protein amylin, upon incubation with rhMMP-9 (100 nM) at 1, 4 and 17 h. Furthermore, Western blots showed a shift in soAβ equilibrium toward lower order, less toxic monomeric species. In conclusion, both MAPK p44/p42 and PKC pathways appear to be involved in histamine-upregulated MMP-9 release via H1Rs in astrocytes. Furthermore, MMP-9 appears to cleave soAβ into less toxic monomeric species. Given the key role of histamine in MMP-9 release, this neurotransmitter may serve as a potential therapeutic target for AD.
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