Dorsal root ganglion neurons innervating skeletal muscle respond to physiological combinations of protons, ATP, and lactate mediated by ASIC, P2X, and TRPV1

J Neurophysiol. 2008 Sep;100(3):1184-201. doi: 10.1152/jn.01344.2007. Epub 2008 May 28.


The adequate stimuli and molecular receptors for muscle metaboreceptors and nociceptors are still under investigation. We used calcium imaging of cultured primary sensory dorsal root ganglion (DRG) neurons from C57Bl/6 mice to determine candidates for metabolites that could be the adequate stimuli and receptors that could detect these stimuli. Retrograde DiI labeling determined that some of these neurons innervated skeletal muscle. We found that combinations of protons, ATP, and lactate were much more effective than individually applied compounds for activating rapid calcium increases in muscle-innervating dorsal root ganglion neurons. Antagonists for P2X, ASIC, and TRPV1 receptors suggested that these three receptors act together to detect protons, ATP, and lactate when presented together in physiologically relevant concentrations. Two populations of muscle-innervating DRG neurons were found. One responded to low metabolite levels (likely nonnoxious) and used ASIC3, P2X5, and TRPV1 as molecular receptors to detect these metabolites. The other responded to high levels of metabolites (likely noxious) and used ASIC3, P2X4, and TRPV1 as their molecular receptors. We conclude that a combination of ASIC, P2X5 and/or P2X4, and TRPV1 are the molecular receptors used to detect metabolites by muscle-innervating sensory neurons. We further conclude that the adequate stimuli for muscle metaboreceptors and nociceptors are combinations of protons, ATP, and lactate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Sensing Ion Channels
  • Adenosine Triphosphate / pharmacology*
  • Amiloride / pharmacology
  • Analysis of Variance
  • Animals
  • Calcium / metabolism
  • Capsaicin / analogs & derivatives
  • Capsaicin / pharmacology
  • Cells, Cultured
  • Cnidarian Venoms / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Ganglia, Spinal / cytology*
  • Hydrogen-Ion Concentration
  • Lactic Acid / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / physiology*
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / physiology*
  • Neurons / drug effects*
  • Neurons / physiology
  • Protons*
  • Purinergic P2 Receptor Antagonists
  • Pyridoxal Phosphate / analogs & derivatives
  • Pyridoxal Phosphate / pharmacology
  • Receptors, Purinergic P2 / physiology*
  • Receptors, Purinergic P2X
  • Sodium Channels / physiology*
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / physiology*


  • APETx2 protein, Anthopleura elegantissima
  • Acid Sensing Ion Channels
  • Cnidarian Venoms
  • Nerve Tissue Proteins
  • Protons
  • Purinergic P2 Receptor Antagonists
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2X
  • Sodium Channels
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid
  • Lactic Acid
  • Pyridoxal Phosphate
  • Amiloride
  • Adenosine Triphosphate
  • capsazepine
  • Capsaicin
  • Calcium