title: TRPM7 kinase activity regulates murine mast cell degranulation.
abstract: The Mg(2+) and Ca(2+) conducting transient receptor potential melastatin 7 (TRPM7) channel-enzyme (chanzyme) has been implicated in immune cell function. Mice heterozygous for a TRPM7 kinase deletion are hyperallergic, while mice with a single point mutation at amino acid 1648, silencing kinase activity, are not. As mast cell mediators trigger allergic reactions, we here determine the function of TRPM7 in mast cell degranulation and histamine release. Our data establish that TRPM7 kinase activity regulates mast cell degranulation and release of histamine independently of TRPM7 channel function. Our findings suggest a regulatory role of TRPM7 kinase activity on intracellular Ca(2+) and extracellular Mg(2+) sensitivity of mast cell degranulation.
  
  
  
  Transient receptor potential melastatin 7 (TRPM7) is a divalent ion channel with a C-terminally located α-kinase. Mice heterozygous for a TRPM7 kinase deletion (TRPM7(+/∆K) ) are hypomagnesaemic and hyperallergic. In contrast, mice carrying a single point mutation at amino acid 1648, which silences TRPM7 kinase activity (TRPM7(KR) ), are not hyperallergic and are resistant to systemic magnesium (Mg(2+) ) deprivation. Since allergic reactions are triggered by mast cell-mediated histamine release, we investigated the function of TRPM7 on mast cell degranulation and histamine release using wild-type (TRPM7(+/+) ), TRPM7(+/∆K) and TRPM7(KR) mice. We found that degranulation and histamine release proceeded independently of TRPM7 channel function. Furthermore, extracellular Mg(2+) assured unperturbed IgE-DNP-dependent exocytosis, independently of TRPM7. However, impairment of TRPM7 kinase function suppressed IgE-DNP-dependent exocytosis, slowed the cellular degranulation rate, and diminished the sensitivity to intracellular calcium (Ca(2+) ) in G protein-induced exocytosis. In addition, G protein-coupled receptor (GPCR) stimulation revealed strong suppression of histamine release, whereas removal of extracellular Mg(2+) caused the phenotype to revert. We conclude that the TRPM7 kinase activity regulates murine mast cell degranulation by changing its sensitivity to intracellular Ca(2+) and affecting granular mobility and/or histamine contents.
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center and University of Hawaii John A. Burns School of Medicine and Cancer Center, Honolulu, HI, 96813, USA.|Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336, Munich, Germany.
authors.forename: Susanna
authors.initials: S
authors.lastname: Zierler
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center and University of Hawaii John A. Burns School of Medicine and Cancer Center, Honolulu, HI, 96813, USA.|Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Colonia Centro CP 91700, Veracruz, Mexico.
authors.forename: Adriana
authors.initials: A
authors.lastname: Sumoza-Toledo
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center and University of Hawaii John A. Burns School of Medicine and Cancer Center, Honolulu, HI, 96813, USA.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336, Munich, Germany.
authors.forename: Fionán Ó
authors.initials: FÓ
authors.lastname: Dúill
authors.affiliation: Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.
authors.forename: Lillia V
authors.initials: LV
authors.lastname: Ryazanova
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center and University of Hawaii John A. Burns School of Medicine and Cancer Center, Honolulu, HI, 96813, USA.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Penner
authors.affiliation: Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Ryazanov
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center and University of Hawaii John A. Burns School of Medicine and Cancer Center, Honolulu, HI, 96813, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fleig
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D050053:TRPM Cation Channels; C421903:Trpm7 protein, mouse