Research Article

Tumor Necrosis Factor Alpha Inhibits L-Type Ca2+ Channels in Sensitized Guinea Pig Airway Smooth Muscle through ERK 1/2 Pathway

Figure 8

Schematic representation of the proposed mode of action of tumor necrosis factor α (TNF-α) on the L-type voltage dependent calcium channel (L-VDCC) of the guinea pig airway smooth muscle. TNF-α whether exogenous or present in sensitized guinea pig serum (Ser-S) activates its receptor 1 (TNFR1). Afterwards, it promotes synthetic signaling pathways: it activates receptor interacting protein (RIP), NF-κB-inducing kinase (NIK), and IκB kinases (IκKs) that phosphorylate NFκB inhibitors (IκBs) activating nuclear factor κB (NFκB) and through TNF receptor-associated factor (TRAF), map kinase kinase (MEK) and extracellular signal-regulated kinase (ERK 1/2), p38 MAPK, or c-Jun N-terminal kinase (JNK). We demonstrated that a synthetic pathway was not responsible for the diminution in the Ca2+ current (ICa, see Figure 4). Nevertheless, ERK 1/2 might be directly phosphorylating    on the subunit of the L-VDCC, favoring a downregulation of the ICa. Inset illustrates ICa in tracheal myocytes and contraction in tracheal rings from guinea pigs. NS implies nonsensitized tissues or cells and this indicates the absence of exogenous TNF-α or serum from Ser-S. S illustrates original recordings from sensitized tissues or cells in the presence of Ser-S; notice that both ICa and contraction are diminished. Other subunits of the L-VDCC: , , γ, δ. SR: sarcoplasmic reticulum.