title: Reductions in external divalent cations evoke novel voltage-gated currents in sensory neurons.
abstract: It has long been recognized that divalent cations modulate cell excitability. Sensory nerve excitability is of critical importance to peripheral diseases associated with pain, sensory dysfunction and evoked reflexes. Thus we have studied the role these cations play on dissociated sensory nerve activity. Withdrawal of both Mg(2+) and Ca(2+) from external solutions activates over 90% of dissociated mouse sensory neurons. Imaging studies demonstrate a Na(+) influx that then causes depolarization-mediated activation of voltage-gated Ca(2+) channels (Ca(V)), which allows Ca(2+) influx upon divalent re-introduction. Inhibition of Ca(V) (ω-conotoxin, nifedipine) or Na(V) (tetrodotoxin, lidocaine) fails to reduce the Na(+) influx. The Ca(2+) influx is inhibited by Ca(V) inhibitors but not by TRPM7 inhibition (spermine) or store-operated channel inhibition (SKF96365). Withdrawal of either Mg(2+) or Ca(2+) alone fails to evoke cation influxes in vagal sensory neurons. In electrophysiological studies of dissociated mouse vagal sensory neurons, withdrawal of both Mg(2+) and Ca(2+) from external solutions evokes a large slowly-inactivating voltage-gated current (I(DF)) that cannot be accounted for by an increased negative surface potential. Withdrawal of Ca(2+) alone fails to evoke I(DF). Evidence suggests I(DF) is a non-selective cation current. The I(DF) is not reduced by inhibition of Na(V) (lidocaine, riluzole), Ca(V) (cilnidipine, nifedipine), K(V) (tetraethylammonium, 4-aminopyridine) or TRPM7 channels (spermine). In summary, sensory neurons express a novel voltage-gated cation channel that is inhibited by external Ca(2+) (IC(50)∼0.5 µM) or Mg(2+) (IC(50)∼3 µM). Activation of this putative channel evokes substantial cation fluxes in sensory neurons.
authors.affiliation: Department of Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Parmvir K
authors.initials: PK
authors.lastname: Bahia
authors.forename: Eric S
authors.initials: ES
authors.lastname: Bennett
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Taylor-Clark
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism*; D002478:Cells, Cultured; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011984:Sensory Receptor Cells / Q000378:metabolism*
chemical_list: D002413:Cations, Divalent; D008274:Magnesium; D002118:Calcium