title: ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons.
abstract: BACKGROUND
  ASIC3, the most sensitive of the acid-sensing ion channels, depolarizes certain rat sensory neurons when lactic acid appears in the extracellular medium. Two functions have been proposed for it: 1) ASIC3 might trigger ischemic pain in heart and muscle; 2) it might contribute to some forms of touch mechanosensation. Here, we used immunocytochemistry, retrograde labelling, and electrophysiology to ask whether the distribution of ASIC3 in rat sensory neurons is consistent with either of these hypotheses.
  
  
  RESULTS
  Less than half (40%) of dorsal root ganglion sensory neurons react with anti-ASIC3, and the population is heterogeneous. They vary widely in cell diameter and express different growth factor receptors: 68% express TrkA, the receptor for nerve growth factor, and 25% express TrkC, the NT3 growth factor receptor. Consistent with a role in muscle nociception, small (<25 microm) sensory neurons that innervate muscle are more likely to express ASIC3 than those that innervate skin (51% of small muscle afferents vs. 28% of small skin afferents). Over 80% of ASIC3+ muscle afferents co-express CGRP (a vasodilatory peptide). Remarkably few (9%) ASIC3+ cells express P2X3 receptors (an ATP-gated ion channel), whereas 31% express TRPV1 (the noxious heat and capsaicin-activated ion channel also known as VR1). ASIC3+/CGRP+ sensory nerve endings were observed on muscle arterioles, the blood vessels that control vascular resistance; like the cell bodies, the endings are P2X3- and can be TRPV1+. The TrkC+/ASIC3+ cell bodies are uniformly large, possibly consistent with non-nociceptive mechanosensation. They are not proprioceptors because they fail two other tests: ASIC3+ cells do not express parvalbumin and they are absent from the mesencephalic trigeminal nucleus.
  
  
  CONCLUSIONS
  Our data indicates that: 1) ASIC3 is expressed in a restricted population of nociceptors and probably in some non-nociceptors; 2) co-expression of ASIC3 and CGRP, and the absence of P2X3, are distinguishing properties of a class of sensory neurons, some of which innervate blood vessels. We suggest that these latter afferents may be muscle metaboreceptors, neurons that sense the metabolic state of muscle and can trigger pain when there is insufficient oxygen.
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, USA. dcm12@pitt.edu
authors.forename: Derek C
authors.initials: DC
authors.lastname: Molliver
authors.forename: David C
authors.initials: DC
authors.lastname: Immke
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fierro
authors.forename: Michel
authors.initials: M
authors.lastname: Paré
authors.forename: Frank L
authors.initials: FL
authors.lastname: Rice
authors.forename: Edwin W
authors.initials: EW
authors.lastname: McCleskey
mesh_terms: D062565:Acid Sensing Ion Channels; D000143:Acids / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000294:innervation / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D009132:Muscles / Q000294:innervation / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism; D020812:Receptor, trkC / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000201:enzymology / Q000378:metabolism*; D012867:Skin / Q000294:innervation / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D000143:Acids; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D020917:Receptor, trkA; D020812:Receptor, trkC; D015740:Calcitonin Gene-Related Peptide