Regulated expression of Na⁺ channels is indispensable to physiological events, whereas dysregulated expression of otherwise silent or even normal Na⁺ channel isoforms causes Na⁺ channelopathies; however, the regulatory mechanisms remain unknown. In quiescent cultured bovine adrenal chromaffin cells, constitutive phosphorylation/activation of extracellular signal-regulated kinase-1 (ERK1) and ERK2 destabilized Na_v l.7 Na⁺ channel alpha-subunit mRNA and decreased its level without altering alpha-subunit gene transcription, thus negatively regulating steady-state level of Na⁺ channels. Activation of protein kinase C (PKC) down-regulated Na⁺ channels via PKC isoform-specific mechanisms; conventional PKC-alpha promoted endocytic internalization of Na⁺ channels, whereas novel PKC-epsilon destabilized alpha-subunit mRNA without altering its gene transcription. Long-lasting (but not short-term) increase of cytoplasmic Ca²⁺ down-regulated Na⁺ channels; a slowly-developing moderate increase of Ca²⁺ activated PKC-alpha and calpain, promoting internalization of Na⁺ channels, whereas an immediate monophasic and salient plateau increase of Ca²⁺ lowered alpha- and beta₁-subunit mRNA levels. Calcineurin, or FK506 binding protein- and rapamycin-associated protein (FRAP), a serine/threonine protein kinase, down-regulated, whereas insulin receptor tyrosine kinase or protein kinase A (PKA) up-regulated, Na⁺ channels via modulating Na⁺ channel internalization, and/or Na⁺ channel externalization from the trans-Golgi network. Neuroprotective, antiepiletic, antipsychotic, and local anesthetic drugs up-regulated Na⁺ channels via transcriptional/translational events.