Potential mechanisms by which sodium channel (Nav) expression is regulated. Neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF) bind to their respective receptors: tyrosine kinase receptor (Trk) A, TrkB, and Ret; receptor stimulation then activates the Ras/MEK/MAPK pathway. Activated MAPK promotes expression of sodium channels at the levels of mRNA and protein through unknown mechanisms (indicated by the red dashed arrows). An inflammatory cytokine, tumor necrosis factor α (TNFα), also up-regulates expression of sodium channels through activation of the TRAF2/MEK/MAPK pathway. In contrast, neurotrophin-3 (NT-3) down-regulates the expression of sodium channels through TrkA-mediated inhibition of the Ras/MEK/MAPK pathway (indicated by the blue dashed arrows). MAPK: mitogen-activated protein kinases; MEK: MAPK kinase; TNFR1: tumor necrosis factor receptor 1; TRAF2: TNF receptor-associated factor 2.