Strong modulation by RFamide neuropeptides of the ASIC1b/3 heteromer in competition with extracellular calcium.
Acid-sensing ion channels are excitatory receptors for extracellular H+. Since the extracellular H+ concentration can significantly increase during an inflammation, one of the proposed functions for ASICs is peripheral perception of pain. The ASIC1b and ASIC3 subunits are specifically expressed in sensory ganglia neurons and are candidate sensors of peripheral acidosis. However, the function of these ASIC subunits is limited by their steady-state desensitization during a small but persistent increase of the H+ concentration and by their desensitization after stronger H+ stimuli. Here we show that ASIC1b and ASIC3 form a heteromeric channel that, at steady-state, desensitizes at more acidic values than either homomeric ASIC1b or homomeric ASIC3 alone. Moreover, we show that RFamide neuropeptides, putative modulators of ASIC activity during inflammation, drastically slow down the desensitization of the ASIC1b/3 heteromer with an apparent dissociation constant of approximately 24microM. The apparent affinity for RFamide-induced effects was about 3-fold higher at low extracellular calcium concentrations. Our results suggest that the ASIC1b/3 heteromer is a possible target for RFamide neuropeptides in the peripheral nervous system.
University of Tübingen, Department of Physiology II, Gmelinstr. 5, 72076 Tübingen, Germany; University of Würzburg, Department of Physiology II, Röntgenring 9, 97070 Würzburg, Germany.
Xuanmao
X
Chen
Martin
M
Paukert
Ivan
I
Kadurin
Michael
M
Pusch
Stefan
S
Gründer
D062565:Acid Sensing Ion Channels; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology*; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
D062565:Acid Sensing Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D015222:Sodium Channels; C058047:arginylphenylalaninamide; D002118:Calcium