title: Histamine induces ATP release from human subcutaneous fibroblasts, via pannexin-1 hemichannels, leading to Ca2+ mobilization and cell proliferation.
abstract: Changes in the regulation of connective tissue ATP-mediated mechano-transduction and remodeling may be an important link to the pathogenesis of chronic pain. It has been demonstrated that mast cell-derived histamine plays an important role in painful fibrotic diseases. Here we analyzed the involvement of ATP in the response of human subcutaneous fibroblasts to histamine. Acute histamine application caused a rise in intracellular Ca(2+) ([Ca(2+)]i) and ATP release from human subcutaneous fibroblasts via H1 receptor activation. Histamine-induced [Ca(2+)]i rise was partially attenuated by apyrase, an enzyme that inactivates extracellular ATP, and by blocking P2 purinoceptors with pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt and reactive blue 2. [Ca(2+)]i accumulation caused by histamine was also reduced upon blocking pannexin-1 hemichannels with (10)Panx, probenecid, or carbenoxolone but not when connexin hemichannels were inhibited with mefloquine or 2-octanol. Brefeldin A, an inhibitor of vesicular exocytosis, also did not block histamine-induced [Ca(2+)]i mobilization. Prolonged exposure of human subcutaneous fibroblast cultures to histamine favored cell growth and type I collagen synthesis via the activation of H1 receptor. This effect was mimicked by ATP and its metabolite, ADP, whereas the selective P2Y1 receptor antagonist, MRS2179, partially attenuated histamine-induced cell growth and type I collagen production. Expression of pannexin-1 and ADP-sensitive P2Y1 receptor on human subcutaneous fibroblasts was confirmed by immunofluorescence confocal microscopy and Western blot analysis. In conclusion, histamine induces ATP release from human subcutaneous fibroblasts, via pannexin-1 hemichannels, leading to [Ca(2+)]i mobilization and cell growth through the cooperation of H1 and P2 (probably P2Y1) receptors.
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Unidade Multidisciplinar de Investigação Biomédica (UMIB); Área Técnico-Científica de Fisioterapia, Escola Superior de Tecnologia da Saúde do Instituto Politécnico do Porto, 4400-330 Vila Nova de Gaia, Portugal.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Pinheiro
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Unidade Multidisciplinar de Investigação Biomédica (UMIB).
authors.forename: Diogo
authors.initials: D
authors.lastname: Paramos-de-Carvalho
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Unidade Multidisciplinar de Investigação Biomédica (UMIB).
authors.forename: Mariana
authors.initials: M
authors.lastname: Certal
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Unidade Multidisciplinar de Investigação Biomédica (UMIB); Departamento de Química, Instituto de Ciências Biomédicas Abel Salazar-Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal.
authors.forename: Maria Adelina
authors.initials: MA
authors.lastname: Costa
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Unidade Multidisciplinar de Investigação Biomédica (UMIB).
authors.forename: Cristina
authors.initials: C
authors.lastname: Costa
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Unidade Multidisciplinar de Investigação Biomédica (UMIB).
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Magalhães-Cardoso
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Unidade Multidisciplinar de Investigação Biomédica (UMIB).
authors.forename: Fátima
authors.initials: F
authors.lastname: Ferreirinha
authors.affiliation: Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Québec, Québec G1V 4G2, Canada; Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, Québec, Québec G1V 0A6, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, Unidade Multidisciplinar de Investigação Biomédica (UMIB). Electronic address: farmacol@icbas.up.pt.
authors.forename: Paulo
authors.initials: P
authors.lastname: Correia-de-Sá
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology; D020126:Brefeldin A / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D017630:Connexins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000378:metabolism / Q000494:pharmacology*; D017442:Histamine Agonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism; D015767:Mefloquine / Q000494:pharmacology; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000442:Octanols / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000962:Antimalarials; D024042:Collagen Type I; D017630:Connexins; D017442:Histamine Agonists; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D009419:Nerve Tissue Proteins; D000442:Octanols; C492764:PANX1 protein, human; D058921:Purinergic P2Y Receptor Antagonists; D011969:Receptors, Histamine H1; D058472:Receptors, Purinergic P2Y1; D020126:Brefeldin A; D000244:Adenosine Diphosphate; C067943:2-octanol; D006632:Histamine; D000255:Adenosine Triphosphate; D002118:Calcium; D015767:Mefloquine
keywords: ADP; ATP; ATP Release; ATPases; Calcium; Human Subcutaneous Fibroblasts; Mechanotransduction; Nucleoside Nucleotide Metabolism; Pannexin; Purinergic Receptor
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