title: Tumor Necrosis Factor Alpha Inhibits L-Type Ca(2+) Channels in Sensitized Guinea Pig Airway Smooth Muscle through ERK 1/2 Pathway.
abstract: Tumor necrosis factor alpha (TNF-α) is a potent proinflammatory cytokine that plays a significant role in the pathogenesis of asthma by inducing hyperresponsiveness and airway remodeling. TNF-α diminishes the L-type voltage dependent Ca(2+) channel (L-VDCC) current in cardiac myocytes, an observation that seems paradoxical. In guinea pig sensitized tracheas KCl responses were lower than in control tissues. Serum from sensitized animals (Ser-S) induced the same phenomenon. In tracheal myocytes from nonsensitized (NS) and sensitized (S) guinea pigs, an L-VDCC current (ICa) was observed and diminished by Ser-S. The same decrease was detected in NS myocytes incubated with TNF-α, pointing out that this cytokine might be present in Ser-S. We observed that a small-molecule inhibitor of TNF-α (SMI-TNF) and a TNF-α receptor 1 (TNFR1) antagonist (WP9QY) reversed ICa decrease induced by Ser-S in NS myocytes, confirming the former hypothesis. U0126 (a blocker of ERK 1/2 kinase) also reverted the decrease in ICa. Neither cycloheximide (a protein synthesis inhibitor) nor actinomycin D (a transcription inhibitor) showed any effect on the TNF-α-induced ICa reduction. We found that CaV1.2 and CaV1.3 mRNA and proteins were expressed in tracheal myocytes and that sensitization did not modify them. In cardiac myocytes, ERK 1/2 phosphorylates two sites of the L-VDCC, augmenting or decreasing ICa; we postulate that, in guinea pig tracheal smooth muscle, TNF-α diminishes ICa probably by phosphorylating the L-VDCC site that reduces its activity through the ERK1/2 MAP kinase pathway.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510 Ciudad de México, DF, Mexico; Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, 04510 Ciudad de México, DF, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Reyes-García
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510 Ciudad de México, DF, Mexico.
authors.forename: Edgar
authors.initials: E
authors.lastname: Flores-Soto
authors.affiliation: Laboratorio de Neurofarmacología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, 14370 Ciudad de México, DF, Mexico.
authors.forename: Héctor
authors.initials: H
authors.lastname: Solís-Chagoyán
authors.affiliation: Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, 14080 Ciudad de México, DF, Mexico.
authors.forename: Bettina
authors.initials: B
authors.lastname: Sommer
authors.affiliation: Departamento de Embriología, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510 Ciudad de México, DF, Mexico.
authors.forename: Verónica
authors.initials: V
authors.lastname: Díaz-Hernández
authors.affiliation: Departamento de Embriología, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510 Ciudad de México, DF, Mexico.
authors.forename: Luz María
authors.initials: LM
authors.lastname: García-Hernández
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510 Ciudad de México, DF, Mexico.
authors.forename: Luis M
authors.identifier: 0000-0002-0065-1298
authors.initials: LM
authors.lastname: Montaño
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D006168:Guinea Pigs; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D014132:Trachea / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D002070:Butadienes; D020746:Calcium Channels, L-Type; D009570:Nitriles; D010456:Peptides, Cyclic; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; C501648:WP9QY peptide; D003609:Dactinomycin; D003513:Cycloheximide