title: Requirement for non-regulated, constitutive calcium influx in macrophage survival signaling.
abstract: The phosphatidylinositol-3-kinase (PI3K)/AKT axis and the Nuclear Factor kappa B (NFκB) pathway play critical roles in macrophage survival. In cells other than macrophages proper operation of those two pathways requires Ca²(+) influx into the cell, but if that is the case in macrophages remains unexplored. In the present work we used THP-1-derived macrophages and a pharmacological approach to examine for the first time the role of constitutive, non-regulated Ca²(+) influx in PI3K/AKT and NFκB signaling. Blocking constitutive function of Ca²(+)-permeable channels with the organic channel blocker SKF96365 completely prevented phosphorylation of IκBα, AKT and its downstream target BAD in TNFα-treated macrophages. A similar effect was observed upon treating macrophages with the calmodulin (CAM) inhibitor W-7 or the calmodulin-dependent kinase II (CAMKII) inhibitor KN-62. In addition, pre-treating macrophages with SKF96365 significantly enhanced TNFα-induced apoptosis. Our findings suggest that in THP-1-derived macrophages survival signaling depends, to a significant extent, on constitutive Ca²(+) influx presumably through a mechanism that involves the CAM/CAMKII axis as a coupling component between constitutive Ca²(+) influx and activation of survival signaling.
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Science Campus, Toledo, OH 43614, USA.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Tano
authors.forename: Guillermo
authors.initials: G
authors.lastname: Vazquez
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002118:Calcium; D002121:Calcium Channel Blockers; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020672:I-kappa B Proteins; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; D000097782:NF-kappaB-Inducing Kinase; C083487:I kappa B beta protein; C063302:KN 62; C017967:W 7; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole