title: The high-affinity immunoglobulin E receptor (FcepsilonRI) regulates mitochondrial calcium uptake and a dihydropyridine receptor-mediated calcium influx in mast cells: Role of the FcepsilonRIbeta chain immunoreceptor tyrosine-based activation motif.
abstract: A growing body of evidence suggests that mitochondria take up calcium upon receptor (agonist) stimulation and that this contributes to the dynamics of spatiotemporal calcium signaling. We have previously shown that engagement of the high-affinity receptor for immunoglobulin E (FcepsilonRI) stimulates mitochondrial calcium ([Ca2+]m) uptake in mast cells. The present study was undertaken to investigate the mechanisms and biological significance of FcepsilonRI regulation of [Ca2+]m. Antigen stimulated [Ca2+]m uptake in a dose-dependent manner with a minimal effective dose of 0.03-3 ng/ml. This [Ca2+]m uptake took place immediately, reaching its peak within minutes and was inhibited by the src family kinase inhibitor PP1 and phosphatidylinositol-3-kinase inhibitor wortmannin. Analyses using mast cells expressing the wild-type or the mutated type of the FcepsilonRIbeta immunoreceptor tyrosine-based activation motif (ITAM) in which all tyrosine residues were replaced by phenylalanine revealed that the FcepsilonRIbeta ITAM is essential for a sustained [Ca2+]m uptake. The FcepsilonRIbeta ITAM was essential for overall calcium response upon weak FcepsilonRI stimulation (at low antigen concentration), while upon strong stimulation (at high antigen concentration) it appeared necessary selectively to an immediate calcium response that was sensitive to the dihydropyridine receptor (DHPR) antagonist nifedipine and wortmannin but not to the store-operated calcium entry (SOCE) antagonists such as 2-aminoethoxyphenyl borate and SK&F96365. These data demonstrate that the FcepsilonRIbeta regulates [Ca2+]m uptake in mast cells via the ITAM and suggest that this plays a key role in regulating calcium influx especially that induced via a DHPR-mediated calcium channel.
authors.affiliation: Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, 30-1 Oyaguchikami-cho Itabashi-ku, Tokyo 173-8610, Japan. ysuzuki@med.nihon-u.ac.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshimaru
authors.forename: Toshio
authors.initials: T
authors.lastname: Inoue
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nunomura
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002417:Cattle; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D008407:Mast Cells / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism*; D017455:Receptors, IgE / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020746:Calcium Channels, L-Type; C521907:Fc-epsilon receptor I beta-chain, mouse; D008565:Membrane Proteins; D017455:Receptors, IgE; C110546:TYROBP protein, human; D002118:Calcium