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 Mg2+ and Ca2+ 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 Ca2+ channels (CaV), which allows Ca2+ influx upon divalent re-introduction. Inhibition of CaV (ω-conotoxin, nifedipine) or NaV (tetrodotoxin, lidocaine) fails to reduce the Na+ influx. The Ca2+ influx is inhibited by CaV inhibitors but not by TRPM7 inhibition (spermine) or store-operated channel inhibition (SKF96365). Withdrawal of either Mg2+ or Ca2+ alone fails to evoke cation influxes in vagal sensory neurons. In electrophysiological studies of dissociated mouse vagal sensory neurons, withdrawal of both Mg2+ and Ca2+ from external solutions evokes a large slowly-inactivating voltage-gated current (IDF) that cannot be accounted for by an increased negative surface potential. Withdrawal of Ca2+ alone fails to evoke IDF. Evidence suggests IDF is a non-selective cation current. The IDF is not reduced by inhibition of NaV (lidocaine, riluzole), CaV (cilnidipine, nifedipine), KV (tetraethylammonium, 4-aminopyridine) or TRPM7 channels (spermine). In summary, sensory neurons express a novel voltage-gated cation channel that is inhibited by external Ca2+ (IC50∼0.5 µM) or Mg2+ (IC50∼3 µM). Activation of this putative channel evokes substantial cation fluxes in sensory neurons.
Highlights
Sensory vagal afferent nerves express specific ion channels that are gated by mechanical, thermal, osmotic, acid/base and chemical stimuli; activation of these ion channels leads to membrane depolarization and the initiation and propagation of action potentials centrally towards the CNS [1]
We repeated these studies in dissociated mouse sensory neurons from the vagal, trigeminal and dorsal root ganglia (DRG) using ratiometric Ca2+ imaging (Fura 2AM)
The neurons were further characterized by their response to capsaicin (a selective transient receptor potential vanilloid receptor 1 (TRPV1) agonist) – a hallmark of nociceptive C-fiber nerves involved in the detection of noxious stimuli [22]
Summary
Sensory vagal afferent nerves express specific ion channels that are gated by mechanical, thermal, osmotic, acid/base and chemical stimuli; activation of these ion channels leads to membrane depolarization and the initiation and propagation of action potentials centrally towards the CNS [1]. Through these mechanisms, multicellular organisms are able to ‘‘sense’’ both their internal and external environment. Extracellular divalent cations contribute substantially to the surface potential of the plasma membrane, effectively modulating the gating of voltage-gated ion channels (e.g. NaV, KV and CaV). Divalent cations directly affect specific ion channels by blocking the peptide pore: for example divalents reduce the conductance of NaV [4]
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