Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.22/3434
Título: Histamine induces ATP release from human subcutaneous fibroblasts via pannexin-1 hemichannels leading to Ca2+ mobilization and cell proliferation
Autor: Pinheiro, Ana Rita
Paramos-de-Carvalho, Diogo
Certal, Mariana
Costa, M. Adelina
Costa, Cristina
Magalhães-Cardoso, Maria Teresa
Ferreirinha, Fátima
Sévigny, Jean
Correia-de-Sá, Paulo
Palavras-chave: ADP
ATP release
Human subcutaneous fibroblasts
Nucleoside nucleotide metabolism
Purinergic receptor
Data: 2013
Editora: The American Society for Biochemistry and Molecular Biology
Relatório da Série N.º: Journal of Biological Chemistry; Vol. 288
Resumo: 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 Ca2+ ([Ca2+]i) and ATP release from human subcutaneous fibroblasts via H1 receptor activation. Histamine-induced [Ca2+]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. [Ca2+]i accumulation caused by histamine was also reduced upon blocking pannexin-1 hemichannels with 10Panx, 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 [Ca2+]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 ADPsensitive 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 [Ca2+]i mobilization and cell growth through the cooperation of H1 and P2 (probably P2Y1) receptors.
Peer review: yes
URI: http://hdl.handle.net/10400.22/3434
Versão do Editor: http://www.jbc.org/content/288/38/27571.full.pdf+html
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