Mitochondrial ligand inhibits store-operated calcium influx and COX-2 production in human microglia.
We used calcium sensitive fluorescence microscopy to investigate the actions of PK11195, a ligand for the mitochondrial peripheral benzodiazepine receptor (PBR), to modulate Ca2+ influx through store-operated channels (SOC) in human microglia. PK11195 effectively blocked SOC-mediated Ca2+ influx induced by platelet-activating factor (PAF) in a dose-dependent manner (IC50 of 9 microM). A prolonged SOC-mediated Ca2+ entry was also induced using the sarcoplasmic endoreticulum Ca2+-ATPase (SERCA) inhibitor cyclopiazonic acid (CPA) to deplete intracellular endoplasmic reticulum (ER) stores; a single concentration of PK11195 (at 20 microM) reduced SOC-mediated Ca2+ influx by 78%. RT-PCR and immunocytochemical analysis results showed PK11195 also inhibited the expression and production of cyclooxygenase-2 (COX-2) triggered by PAF stimulation. These results suggest that activation of the PBR in mitochondria is linked to reduced entry of Ca2+ through plasmalemmal SOC and subsequent modulation of cellular functions in human microglia.
Department of Pharmacology and Therapeutics, Department of Medicine, University of British Columbia, Vancouver, Canada.
Seok H
SH
Hong
Hyun B
HB
Choi
Seung U
SU
Kim
James G
JG
McLarnon
D000970:Antineoplastic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
D000970:Antineoplastic Agents; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D007211:Indoles; D007546:Isoquinolines; D008024:Ligands; D008565:Membrane Proteins; D010972:Platelet Activating Factor; D012333:RNA, Messenger; D018079:Receptors, GABA; C499229:TSPO protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; C000543:cyclopiazonic acid; C037850:PK 11195