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1 Internal Medicine, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
2 Psychiatry, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
3 Howard Hughes Medical Institute, Iowa City, IA, USA; Internal Medicine, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
4 Howard Hughes Medical Institute, Iowa City, IA, USA; Internal Medicine, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA; Physiology and Biophysics, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
* To whom correspondence should be addressed. E-mail: michael-welsh{at}uiowa.edu.
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.
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