Voltage-dependent Nav1.7 sodium channels: Multiple roles in adrenal chromaffin cells and peripheral nervous system

Voltage-dependent Na⁺ channels consist of the principal α-subunit (∼260 kDa), without or with auxiliary β-subunit (∼38 kDa). Nine α-subunit isoforms (Na_v1.1-Na _v1.9) are encoded in nine different genes (SCN1A-SCN5A and SCN8A-SCN11A). Besides initiating and propagating action potentials in established neuronal circuit, Na⁺ channels engrave, maintain and repair neuronal network in the brain throughout the life. Adrenal chromaffin cells express Na_v1.7 encoded in SCN9A, which is widely distributed among peripheral autonomic and sensory ganglia, neuroendocrine cells, as well as prostate cancer cell lines. In chromaffin cells, Na_v1.7-specific biophysical properties have been characterized; physiological stimulation by acetylcholine produces muscarinic receptor-mediated hyperpolarization followed by nicotinic receptor-mediated depolarization. In human patients with Na _v1.7 channelopathies, gain-of-pathological function mutants (i.e. erythermalgia and paroxysmal extreme pain disorder) or loss-of-physiological function mutant (channelopathy-associated insensivity to pain) proved the causal involvement of mutant Na_v1.7 in generating intolerable pain syndrome, Na_v1.7 being the first molecular target convincingly identified for pain treatment. Importantly, aberrant upregulation/hyperactivity of even the native Na_v1.7 produces pain associated with inflammation, nerve injury and diabetic neuropathy in rodents. Various extra- and intracellular signals, as well as therapeutic drugs modulate the activity of Na_v1.7, and also cause up- and downregulation of Na_v1.7. Na_v1.7 seems to play an increasing number of crucial roles in health, disease and therapeutics. © 2008 The Authors.