Voltage-dependent Na(v)1.7 sodium channels: multiple roles in adrenal chromaffin cells and peripheral nervous system.
Voltage-dependent Na+ channels consist of the principal alpha-subunit (approximately 260 kDa), without or with auxiliary beta-subunit (approximately 38 kDa). Nine alpha-subunit isoforms (Na(v)1.1-Na(v)1.9) 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(v)1.7 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(v)1.7-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(v)1.7 channelopathies, gain-of-pathological function mutants (i.e. erythermalgia and paroxysmal extreme pain disorder) or loss-of-physiological function mutant (channelopathy-associated insensitivity to pain) proved the causal involvement of mutant Na(v)1.7 in generating intolerable pain syndrome, Na(v)1.7 being the first molecular target convincingly identified for pain treatment. Importantly, aberrant upregulation/hyperactivity of even the native Na(v)1.7 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(v)1.7, and also cause up- and downregulation of Na(v)1.7. Na(v)1.7 seems to play an increasing number of crucial roles in health, disease and therapeutics.
Wada
A
A
Department of Pharmacology, Miyazaki Medical College, University of Miyazaki, Miyazaki, Japan. akihiko@fc.miyazaki-u.ac.jp
Wanke
E
E
Gullo
F
F
Schiavon
E
E
D000818:Animals; D053447:Channelopathies / Q000378:metabolism; D019439:Chromaffin Cells / Q000378:metabolism*; D004594:Electrophysiology; D006801:Humans; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010146:Pain / Q000378:metabolism; D017288:Pain Threshold; D018408:Patch-Clamp Techniques; D017933:Peripheral Nervous System / Q000378:metabolism*; D051381:Rats; D011950:Receptors, Cholinergic / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*
D062556:NAV1.7 Voltage-Gated Sodium Channel; D011950:Receptors, Cholinergic; C503480:Scn9a protein, rat; D015222:Sodium Channels