ASIC2a and ASIC3 heteromultimerize to form pH-sensitive channels in mouse cardiac dorsal root ganglia neurons.
BACKGROUND
Acid-sensing ion channels (ASICs) are Na+ channels that are activated by acidic pH. Their expression in cardiac afferents and remarkable sensitivity to small pH changes has made them leading candidates to sense cardiac ischemia.


OBJECTIVE
Four genes encode six different ASIC subunits, however it is not yet clear which of the ASIC subunits contribute to the composition of ASICs in cardiac afferents.


RESULTS
Here, we labeled cardiac afferents using a retrograde tracer dye in mice, which allowed for patch-clamp studies of murine cardiac afferents. We found that a higher percentage of cardiac sensory neurons from the dorsal root ganglia respond to acidic pH and generated larger currents compared to those from the nodose ganglia. The ASIC-like current properties of the cardiac dorsal root ganglia neurons from wild-type mice most closely matched the properties of ASIC2a/3 heteromeric channels. This was supported by studies in ASIC-null mice: acid-evoked currents from ASIC3(-/-) cardiac afferents matched the properties of ASIC2a channels, and currents from ASIC2(-/-) cardiac afferents matched the properties of ASIC3 channels.


CONCLUSIONS
We conclude that ASIC2a and -3 are the major ASIC subunits in cardiac dorsal root ganglia neurons and provide potential molecular targets to attenuate chest pain and deleterious reflexes associated with cardiac disease.
Hattori
Tomonori
T
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Chen
Jie
J
Harding
Anne Marie S
AM
Price
Margaret P
MP
Lu
Yongjun
Y
Abboud
Francois M
FM
Benson
Christopher J
CJ
D062565:Acid Sensing Ion Channels; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006321:Heart / Q000294:innervation*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D055503:Protein Multimerization / Q000502:physiology*; D011522:Protons; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
C568265:ASIC2 protein, mouse; C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; D011522:Protons; D015222:Sodium Channels; D000255:Adenosine Triphosphate; D002211:Capsaicin