title: Impairment of survival signaling and efferocytosis in TRPC3-deficient macrophages.
abstract: We have recently shown that in macrophages proper operation of the survival pathways phosphatidylinositol-3-kinase (PI3K)/AKT and nuclear factor kappa B (NFkB) has an obligatory requirement for constitutive, non-regulated Ca(2+) influx. In the present work we examined if Transient Receptor Potential Canonical 3 (TRPC3), a member of the TRPC family of Ca(2+)-permeable cation channels, contributes to the constitutive Ca(2+) influx that supports macrophage survival. We used bone marrow-derived macrophages obtained from TRPC3(-/-) mice to determine the activation status of survival signaling pathways, apoptosis and their efferocytic properties. Treatment of TRPC3(+/+) macrophages with the pro-apoptotic cytokine TNFα induced time-dependent phosphorylation of IκBα, AKT and BAD, and this was drastically reduced in TRPC3(-/-) macrophages. Compared to TRPC3(+/+) cells TRPC3(-/-) macrophages exhibited reduced constitutive cation influx, increased apoptosis and impaired efferocytosis. The present findings suggest that macrophage TRPC3, presumably through its constitutive function, contributes to survival signaling and efferocytic properties.
authors.affiliation: Department of Physiology and Pharmacology and the Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Health Science Campus, 3000 Arlington Av, Toledo, OH 43614, USA.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Tano
authors.forename: Kathryn
authors.initials: K
authors.lastname: Smedlund
authors.forename: Robert
authors.initials: R
authors.lastname: Lee
authors.forename: Joel
authors.initials: J
authors.lastname: Abramowitz
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Guillermo
authors.initials: G
authors.lastname: Vazquez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D020672:I-kappa B Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: C494820:Bad protein, mouse; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D014409:Tumor Necrosis Factor-alpha; D051025:bcl-Associated Death Protein; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium