Neuropeptides are small signaling molecules produced and released by neurons engaged in many physiological functions. Indeed,neuropeptides act on neural substrates such as G protein-coupled receptors (GPCRs),tyrosine-kinase receptors,insuline-like peptides and also ion channels. Actions of neuropeptides result in slow-onset,long-lasting modulation of synaptic transmission.
Pro-FMRFamide-related neuropeptide VF
Pro-FMRFamide-related neuropeptide VF also called neuropeptide VF precursor are expressed in neurons in mediobasal hypothalamus. Neuropeptide VF precursor is a propeptide which is cleaved in three others peptide: Neuropeptide RFRP-1,RFRP-2 and RFRP-3.
Neuropeptide RFRP-2 (101-112)
Neuropeptide RFRP-2 (101-112) is very interesting because RFRP-2 shows no inhibitory activity and RFRP-2 sequence is absent in mouse and rat.
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.
2- DeLaney K. et al. J Exp Biol. 221(Pt 3):jeb151167 (2018)
Neuropeptides are one of the most diverse classes of signaling molecules and have attracted great interest over the years owing to their roles in regulation of a wide range of physiological processes. However,there are unique challenges associated with neuropeptide studies stemming from the highly variable molecular sizes of the peptides,low in vivo concentrations,high degree of structural diversity and large number of isoforms. As a result,much effort has been focused on developing new techniques for studying neuropeptides,as well as novel applications directed towards learning more about these endogenous peptides. The areas of importance for neuropeptide studies include structure,localization within tissues,interaction with their receptors,including ion channels,and physiological function. Here,we discuss these aspects and the associated techniques,focusing on technologies that have demonstrated potential in advancing the field in recent years. Most identification and structural information has been gained by mass spectrometry,either alone or with confirmations from other techniques,such as nuclear magnetic resonance spectroscopy and other spectroscopic tools. While mass spectrometry and bioinformatic tools have proven to be the most powerful for large-scale analyses,they still rely heavily on complementary methods for confirmation. Localization within tissues,for example,can be probed by mass spectrometry imaging,immunohistochemistry and radioimmunoassays. Functional information has been gained primarily from behavioral studies coupled with tissue-specific assays,electrophysiology,mass spectrometry and optogenetic tools. Concerning the receptors for neuropeptides,the discovery of ion channels that are directly gated by neuropeptides opens up the possibility of developing a new generation of tools for neuroscience,which could be used to monitor neuropeptide release or to specifically change the membrane potential of neurons. It is expected that future neuropeptide research will involve the integration of complementary bioanalytical technologies and functional assays.
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