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.
FMRFamide is a neuropeptide that is part of the family of FMRFamide-related peptides. Several FMRFamide-related peptides are involved in various cellular regulation and have shown pharmacological actions, such as anti-opiate effects. FMRFamide plays an important role in cardiac activity regulation in Hard clam.
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1- Raffa R. B. Peptides. 9(4):915-922 (1988)
First purified 11 years ago from clam ganglia, FMRFamide (Phe-Met-Arg-Phe-NH2) was quickly demonstrated to be cardioactive in several molluscan species. Subsequent discovery that FMRFamide, or FMRFamide-related peptides (FaRPs), were present in mammalian central nervous system and gastrointestinal tract prompted investigations into the effect of FMRFamide on mammals. FMRFamide has now been shown to be cardioexcitatory in mammals, to inhibit morphine-induced antinociception, and to block morphine-, defeat-, and deprivation-induced feeding. It also inhibits colonic propulsive motility, induces behavioral effects when administered intrathecally, and has been reported to have amnesic effects in rodents. A proposal has arisen that a FMRFamide-like substance is an endogenous opioid antagonist and has stimulated a search for such a substance. However, FMRFamide has only weak affinity for opioid receptors and not all the actions of FMRFamide appear to be explained by actions at opioid receptors. Alternative mechanisms have been proposed which suggest that FMRFamide acts as a neuromodulator.
2- Coscoy S, Lingueglia E, Lazdunski M and Barbry P. J Biol Chem. 273(14):8317-22 (1998)
The Helix aspersa Phe-Met-Arg-Phe-amide (FMRFamide)-gated sodium channel is formed by homomultimerization of several FMRFamide-activated Na+ channel (FaNaCh) proteins. FaNaCh is homologous to the subunits that compose the amiloride-sensitive epithelial sodium channel, to Caenorhabditis elegans degenerins, and to acid-sensing ionic channels. FaNaCh properties were analyzed in stably transfected human embryonic kidney cells (HEK-293). The channel was functional with an EC50 for FMRFamide of 1 microM and an IC50 (25 degreesC) for amiloride of 6.5 microM as assessed by 22Na+ uptake measurements. The channel activity was associated with the presence of a protein at the cell surface with an apparent molecular mass of 82 kDa. The 82-kDa form was derived from an incompletely glycosylated form of 74 kDa found in the endoplasmic reticulum. Formation of covalent bonds between subunits of the same complex were observed either after formation of intersubunit disulfide bonds following cell homogenization and solubilization with Triton X-100 or after use of bifunctional cross-linkers. This resulted in the formation of covalent multimers that contained up to four subunits. Hydrodynamic properties of the solubilized FaNaCh complex also indicated a maximal stoichiometry of four subunits per complex. It is likely that epithelial Na+ channels, acid-sensing ionic channels, degenerins, and the other proteins belonging to the same ion channel superfamily also associate within tetrameric complexes.
3- Cottrell G A, Green K A and Davies N W. Pflugers Arch. 416(5):612-614 (1990)
The neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) can activate a ligand-gated ion channel in Helix neurones
This report presents evidence that the molluscan neuropeptide FMRFamide can directly activate a ligand-gated ion channel in Helix neurones. Using the patch-clamp technique we have observed unitary currents activated by the application of FMRFamide onto outside-out patches. As for the whole-cell response, Na+ ions are the main charge carriers. We conclude that FMRFamide may act as a fast depolarizing neurotransmitter in the Helix nervous system.
4- Li C, Kim K and Nelson L S. Brain Res. 848(1-2):26-34 (1999)
Neuropeptides are used as signaling molecules in the nervous system of most organisms, including mammals. The family of FMRFamide (Phe-Met-Arg-Phe-NH2)-like neuropeptides (FaRPs) all share an RFamide sequence at their C-termini and have been shown to have diverse functions in the central and peripheral nervous systems. In the nematode Caenorhabditis elegans, FMRFamide-like peptides (FaRPs) are expressed in at least 10% of the neurons, including motor, sensory, and interneurons that are involved in movement, feeding, defecation, and reproduction. Twenty-two genes, designated flp-1 through flp-22, encode FaRPs in C. elegans, although there are likely to be additional flp genes to be identified. Each flp gene encodes a different set of FaRPs, yielding a predicted total of 59 distinct FaRPs; a few of the genes may also encode non-FaRPs. Inactivation of some of the flp genes indicates that at least one flp gene has unique functions, while at least two flp genes appear to have overlapping functions with other flp genes. These results suggest that a complex family of FaRPs have varied roles through all stages of development and in adulthood in C. elegans.
5- 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.