FMRFamide and Analogs

Definition
FMRFamide is a molluscan neuroactive peptide which induces a fast excitatory depolarizing response due to direct activation of amiloride-sensitive sodium channels1.

Related peptides
FLRFamide, LFRFamide, FFRFamide, LLRFamide, D-FMRFamide, are FMRFamide analogs that have been found to exhibit a cross-interaction with FMRFamide. It is possible that these peptides also act on the same class of RFamide receptors as agonists to cause cross desensitization2. Two invertebrate neuropeptide analogues, IPPQFMRF amide (IF-8 amide) and EGDEDEFLRF amide (EF-10 amide), from the defensive skin secretions of two different species of African hyperoliid frogs, Kassina maculata and Phylictimantis verrucosus, respectively, represent the first canonical FMRF amide-related peptides (FaRPs) from a vertebrate source3.

Discovery
The first FMRF-amide was isolated in 1977 as a cardioexcitatory molecule from the clam Macrocallista nimbosa, by DA Price and MJ Greenberg4.

Structural Characteristics
It is a tetrapeptide neurotransmitter, a member of the same family of RFamide peptides as FLRFamide, sharing the same C terminal RFamide sequence. The structure of FMRFamide was first determined by the combined use of Edman dansyl degradation and tryptic digestion and confirmed by synthesis5.

Structure-activity relations (SAR) of FMRFamide on the isolated Rapana heart5 have shown that:
(1) The C-terminal RFamide is critical for activity; potency is markedly diminished by substitution with D amino acids and is abolished upon removal of the amide.
(2) The N-terminal phenylalanine and the methionine could be replaced by other residues, but a total length of at least four residues is important for activity.
(3) N-terminal elongation may have little effect.
(4) FMRFamide was the most potent of 14 peptides tested6.

Mode of Action
It has been reported that FMRFamides exert their effect by directly activating FMRFamide-gated sodium channels without involvement of a G protein. However, earlier electrophysiological studies in molluscs suggested that FMRFamide could also activate a GPCR6.

Functions
FMRFamides act as neurotransmitters/neuromodulators within the larval and adult CNS, as well as at selected peripheral targets. The latter include, for example, tissues associated with feeding (gut, salivary glands), reproduction (accessory glands, spermatheca, and oviducts), movement (skeletal muscle), circulation (aorta), and ecdysis (coordinated modulation of visceral and skeletal muscles) 6.

References
1.Lingueglia E, Champigny G, Lazdunski M, Barbry P (1995). Cloning of the amiloride-sensitive FMRFamide peptide-gated sodium channel. Nature, 378(6558):730-733.
2.Chen ML, Sharma R, Walker RJ (1995). Structure-activity studies of RFamide analogues on central neurones of Helix aspersa. Regulatory peptides,58:99-105.
3.Wang L, Smyth A, Johnsen AH, Zhou M, Chen T, Walker B, Shaw C (2009). FMRFamide-related peptides (FaRPs): A new family of peptides from amphibian defensive skin secretions. BBRC, 383(3):314-319
4.Price DA, Greenberg MJ (1977). Structure of a molluscan cardioexcitatory neuropeptide. Science, 197(4304):670-671.
5.Kobayashi M , Muneoka Y (1989). Functions, Receptors, and Mechanisms of the FMRFamide-Related Peptides. Biol. Bull, 177: 206-209.
6.Meeusen T, Mertens I, Clynen E, Baggerman G, Nichols R, Nachman RJ, Huybrechts R, De Loof A, Schoofs L (2002). Identification in Drosophila melanogaster of the invertebrate G protein-coupled FMRFamide receptor. PNAS, 99(24):15363-15368.