title: ASIC3 and ASIC1 mediate FMRFamide-related peptide enhancement of H+-gated currents in cultured dorsal root ganglion neurons.
abstract: The acid-sensing ion channels (ASICs) form cation channels that are transiently activated by extracellular protons. They are expressed in dorsal root ganglia (DRG) neurons and in the periphery where they play a function in nociception and mechanosensation. Previous studies showed that FMRFamide and related peptides potentiate H(+)-gated currents. To better understand this potentiation, we examined the effect of FMRFamide-related peptides on DRG neurons from wild-type mice and animals missing individual ASIC subunits. We found that FMRFamide and FRRFamide potentiated H(+)-gated currents of wild-type DRG in a dose-dependent manner. They increased current amplitude and slowed desensitization following a proton stimulus. Deletion of ASIC3 attenuated the response to FMRFamide-related peptides, whereas the loss of ASIC1 increased the response. The loss of ASIC2 had no effect on FMRFamide-dependent enhancement of H(+)-gated currents. These data suggest that FMRFamide-related peptides modulate DRG H(+)-gated currents through an effect on both ASIC1 and ASIC3 and that ASIC3 plays the major role. The recent discovery of RFamide-related peptides (RFRP) in mammals suggested that they might also modulate H(+)-gated current. We found that RFRP-1 slowed desensitization of H(+)-gated DRG currents, whereas RFRP-2 increased the peak amplitude. COS-7 cells heterologously expressing ASIC1 or ASIC3 showed similar effects. These results suggest that FMRFamide-related peptides, including the newly identified RFRPs, modulate H(+)-gated DRG currents through ASIC1 and ASIC3. The presence of several ASIC subunits, the diversity of FMRFamide-related peptides, and the distinct effects on H(+)-gated currents suggest the possibility of substantial complexity in modulation of current in DRG sensory neurons.
authors.affiliation: Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Xie
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Price
authors.forename: John A
authors.initials: JA
authors.lastname: Wemmie
authors.forename: Candice C
authors.initials: CC
authors.lastname: Askwith
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
mesh_terms: D062565:Acid Sensing Ion Channels; D000818:Animals; D002478:Cells, Cultured; D019835:FMRFamide / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects*; D008565:Membrane Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*
chemical_list: C568266:ASIC1 protein, human; C568267:ASIC1 protein, mouse; C568265:ASIC2 protein, mouse; C112231:ASIC3 protein, human; D062565:Acid Sensing Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D019835:FMRFamide