Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli. J Neurosci 2005 Oct 26;25(43):9893-901
Date
10/28/2005Pubmed ID
16251436Pubmed Central ID
PMC6725570DOI
10.1523/JNEUROSCI.2019-05.2005Scopus ID
2-s2.0-27344452734 (requires institutional sign-in at Scopus site) 110 CitationsAbstract
Molecular and behavioral evidence suggests that acid-sensing ion channels (ASICs) contribute to pain processing, but an understanding of their precise role remains elusive. Existing ASIC knock-out mouse experiments are complicated by the heteromultimerization of ASIC subunits. Therefore, we have generated transgenic mice that express a dominant-negative form of the ASIC3 subunit that inactivates all native neuronal ASIC-like currents by oligomerization. Using whole-cell patch-clamp recordings, we examined the response properties of acutely isolated dorsal root ganglion neurons to protons (pH 5.0). We found that whereas 33% of the proton-responsive neurons from wild-type mice exhibited an ASIC-like transient response, none of the neurons from the transgenic mice exhibited a transient inward current. Capsaicin-evoked responses mediated by the TRPV1 receptor were unaltered in transgenic mice. Adult male wild-type and transgenic mice were subjected to a battery of behavioral nociceptive assays, including tests of thermal, mechanical, chemical/inflammatory, and muscle pain. The two genotypes were equally sensitive to thermal pain and to thermal hypersensitivity after inflammation. Compared with wild types, however, transgenic mice were more sensitive to a number of modalities, including mechanical pain (von Frey test, tail-clip test), chemical/inflammatory pain (formalin test, 0.6% acetic acid writhing test), mechanical hypersensitivity after zymosan inflammation, and mechanical hypersensitivity after intramuscular injection of hypotonic saline. These data reinforce the hypothesis that ASICs are involved in both mechanical and inflammatory pain, although the increased sensitivity of transgenic mice renders it unlikely that they are direct transducers of nociceptive stimuli.
Author List
Mogil JS, Breese NM, Witty MF, Ritchie J, Rainville ML, Ase A, Abbadi N, Stucky CL, Séguéla PAuthor
Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Acid Sensing Ion ChannelsAnimals
Behavior, Animal
Blotting, Northern
Capsaicin
Cell Line
Cloning, Molecular
Cricetinae
Ganglia, Spinal
Gene Expression Regulation
Humans
Hydrogen-Ion Concentration
Inflammation
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutagenesis
Nerve Tissue Proteins
Neurons
Oocytes
Pain Measurement
Patch-Clamp Techniques
Physical Stimulation
Protein Structure, Tertiary
Protein Subunits
Protons
RNA, Messenger
Reaction Time
Reverse Transcriptase Polymerase Chain Reaction
Sodium Channels
Time Factors
Transfection
Xenopus
