Abstract
Acid-sensing ion channels (ASICs) belong to the DEG/ENaC gene family. While ASIC1a, ASIC1b and ASIC3 are activated by extracellular protons, ASIC4 and the closely related bile acid-sensitive ion channel (BASIC or ASIC5) are orphan receptors. Neuropeptides are important modulators of ASICs. Moreover, related DEG/ENaCs are directly activated by neuropeptides, rendering neuropeptides interesting ligands of ASICs. Here, we performed an unbiased screen of 109 short neuropeptides (<20 amino acids) on five homomeric ASICs: ASIC1a, ASIC1b, ASIC3, ASIC4 and BASIC. This screen revealed no direct agonist of any ASIC but three modulators. First, dynorphin A as a modulator of ASIC1a, which increased currents of partially desensitized channels; second, YFMRFamide as a modulator of ASIC1b and ASIC3, which decreased currents of ASIC1b and slowed desensitization of ASIC1b and ASIC3; and, third, endomorphin-1 as a modulator of ASIC3, which also slowed desensitization. With the exception of YFMRFamide, which, however, is not a mammalian neuropeptide, we identified no new modulator of ASICs. In summary, our screen confirmed some known peptide modulators of ASICs but identified no new peptide ligands of ASICs, suggesting that most short peptides acting as ligands of ASICs are already known.
Highlights
Acid-sensing ion channels form a small family of proton-gated ion channels that belongs to the degenerin/epithelial Na+ channel (DEG/ENaC) gene family[1]
Our study was motivated by the question whether short neuropeptides act as direct agonists of Acid-sensing ion channels (ASICs), with an emphasis on the orphan receptors ASIC4 and bile acid-sensitive ion channel (BASIC)
Since the peptides that activate established peptide-gated DEG/ENaCs contain four (FMRFamide, the ligand of FMRFamide-activated Na+ channel (FaNaC))[17], seven (Hydra-RFamides, the ligands of Hydra Na+ channels (HyNaCs))[18] or nine to ten amino acids[20], and to limit the financial costs of our screen, we restricted it to peptides that contain less than 20 amino acids
Summary
Acid-sensing ion channels form a small family of proton-gated ion channels that belongs to the degenerin/epithelial Na+ channel (DEG/ENaC) gene family[1]. Homomeric ASIC2b, a splice variant of ASIC2a, is not activated by low pH, but contributes to heteromeric channels[8]. FMRFamide and several FMRFamide-related peptides, including the mammalian neuropeptides FF (NPFF; FLFQPQRFamide) and AF (NPAF; AGEGLSSPFWSLAAPQRFamide)[12] and the conorfamide RPRFamide[13], probably bind to a cavity in the lower palm domain[14] and slow desensitization of ASIC312,13. Other channels in the DEG/ENaC gene family are directly activated by neuropeptides. Modulation of ASICs by neuropeptides and direct activation of peptide-gated DEG/ENaCs by neuropeptides render peptides candidate agonists for ASIC4 and BASIC. First, whether any of the 109 peptides could directly activate ASICs, in particular ASIC4 and BASIC, and, second, whether any of the 109 peptides modulated gating of homomeric ASIC1a, homomeric ASIC1b or homomeric ASIC3
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