FMRFa Gene (FMRFamide-Related Neuropeptide Precursor) – Functional Annotation Report OpenAI o3-deep-research-2025-06-26 74 citations 2026-05-01T14:05:45.418957

FMRFa Gene (FMRFamide-Related Neuropeptide Precursor) – Functional Annotation Report

Gene and Protein Overview

FMRFa in Sepia officinalis encodes a precursor protein that is processed into multiple FMRFamide-related peptides (FaRPs). FMRFamide (Phe-Met-Arg-Phe-NH₂) is a hallmark tetrapeptide neuropeptide originally discovered in mollusks in 1977 (www.frontiersin.org). The S. officinalis FMRFa gene belongs to the FaRP peptide family (UniProt P91889) and produces a ~331 amino acid precursor (~39 kDa) containing an N-terminal signal peptide and numerous repeated neuropeptide sequences (pmc.ncbi.nlm.nih.gov). Proteolytic processing of this precursor yields at least four distinct neuropeptides, including single copies of FLRFamide, ALSGDAFLRFamide, FIRFamide, and multiple copies (∼11 repeats in cuttlefish) of FMRFamide itself (pmc.ncbi.nlm.nih.gov) (www.sciencedirect.com). A conserved furin cleavage site (RX[K/R]R) separates the precursor into regions, facilitating the liberation of the active C-terminal RFamide peptides (www.frontiersin.org). These peptides all share the C-terminal –RFamide motif, characteristic of this neuropeptide family.

Conservation and Family – FMRFamide and related RFamide peptides are evolutionarily widespread. Since its initial characterization as a cardio-excitatory neuropeptide in clams, RFamide peptides have been identified across diverse phyla – from cnidarians to arthropods and chordates (pmc.ncbi.nlm.nih.gov). In mollusks, the FMRFa gene is one of five major RFamide precursor genes, alongside LFRFamide, luqin, neuropeptide F, and others (www.frontiersin.org). Notably, insects like Drosophila also possess an FMRFamide gene (sometimes denoted FMRFa), encoding similar neuropeptides – underscoring the conserved role of RFamide signaling in invertebrate nervous systems. (This report focuses on the S. officinalis FMRFa; care is taken not to confuse it with homologs in other species.)

Expression and Localization

Cellular Localization: The FMRFa precursor contains a signal peptide directing it into the secretory pathway (pmc.ncbi.nlm.nih.gov). It is packaged in neurosecretory vesicles and cleaved into active peptides that are secreted as neurotransmitters or neurohormones. Thus, the mature peptides function extracellularly, binding to receptors on target cells. Within neurons, FMRFamide peptides are often localized to dense-core vesicles in synapses or neurohemal release sites.

Tissue Distribution: Expression of FMRFa is highly central nervous system (CNS)-enriched. A 2018 analysis in a related cuttlefish (Sepiella japonica) showed highest FMRFa mRNA levels in the brain (in both sexes) compared to other tissues (pmc.ncbi.nlm.nih.gov). In S. officinalis, in situ hybridization and immunochemical studies have similarly found FMRFa transcripts and peptides widely distributed across brain lobes (pmc.ncbi.nlm.nih.gov). FMRFamide immunoreactivity is present in many neural circuits of the supraesophageal and subesophageal masses (the cephalopod brain regions) (pmc.ncbi.nlm.nih.gov). Peripheral nervous structures also contain FMRFamide-expressing neurons; for example, FMRFamide-positive fibers innervate the optic gland, viscera, and peripheral nerves (www.frontiersin.org). Notably, FMRFamide-like peptides are present in the venous blood of cephalopods, indicating neurohormonal release into circulation (www.frontiersin.org). Recent evidence even suggests expression outside the nervous system: immune cells (hemocytes) of molluscs can express and synthesize FMRFamide peptides (www.frontiersin.org). In cuttlefish and octopus, FMRFamide-expressing neurons project to endocrine glands (optic gland) and peripheral organs, underscoring a neuroendocrine role (www.frontiersin.org).

Subcellular Localization: Within neurons, the FMRFa precursor is processed in the Golgi and packaged in secretory granules. The mature peptides are stored in synaptic terminals or neurohemal areas until stimulus-triggered release. In target cells, FMRFamide receptors are membrane-bound (GPCRs or ion channels, discussed below). For instance, a specialized FMRFamide-gated Na⁺ channel cloned from S. japonica (SjFaNaC) was shown to localize to the cell surface when expressed in HEK293 cells (pubmed.ncbi.nlm.nih.gov), consistent with it being an extracellular ligand receptor.

Molecular Function and Mechanisms

Neuropeptide Signaling: FMRFa’s gene product is fundamentally a neurotransmitter/neuromodulator precursor. The liberated FMRFamide peptides bind to specific receptors on neurons or muscle cells to modulate their activity. These peptides are considered important neurotransmitters or neuromodulators in invertebrates, influencing a wide range of neural and physiological processes (pmc.ncbi.nlm.nih.gov).

Receptors and Pathways: Two main types of FMRFamide receptors are known in invertebrates: G protein-coupled receptors and ligand-gated ion channels. Most commonly, FMRFamide-related peptides signal through G-protein coupled receptors (GPCRs) on target cell membranes (www.sciencedirect.com). Binding of FMRFamide to its GPCR triggers intracellular second messenger cascades (e.g. via G_q or G_i pathways), ultimately altering neuronal excitability or cellular responses (www.sciencedirect.com). For example, FMRFamide receptors in mollusks are related to the neuropeptide FF receptor family and initiate signaling that modulates ion channel activity and gene expression. Sepiella cuttlefish were recently found to possess an FMRFamide GPCR (418 amino acids, seven-transmembrane structure) expressed in neural tissues (www.sciencedirect.com). This receptor (SjFaGPCR) is thought to mediate many of the peptide’s physiological effects, such as reproductive maturation signals (www.sciencedirect.com).

Unusually, FMRFamide can also act directly on ion channels. A family of FMRFamide-activated Na⁺ channels (FaNaCs) has been characterized in mollusks (pubmed.ncbi.nlm.nih.gov). These are non-voltage-gated, amiloride-sensitive sodium channels opened by FMRFamide binding, causing rapid depolarization of neurons. The S. japonica FaNaC channel (603 amino acids) is conserved in cephalopods and highly expressed in the brain and optic lobe, as well as in gonadal tissue (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). FaNaCs provide a fast, excitatory mechanism for FMRFamide signaling, complementing the slower GPCR-mediated modulation. In molluscan neurons (e.g. in snails), FMRFamide can inhibit neural activity by other means as well – for instance, by modulating ion conductances via second messengers. In Aplysia neurons, FMRFamide was shown to open K⁺ channels and reduce Ca²⁺ currents, rapidly terminating bursting activity (pubmed.ncbi.nlm.nih.gov). Thus, depending on context, FMRFamide peptides can either excite or inhibit target cells through distinct mechanisms – direct channel gating or G-protein signaling – ultimately tuning neuronal circuit activity.

Biological Roles and Processes

1. Neuromodulation and Behavior: As a broadly expressed neuropeptide, FMRFamide influences many neural circuits and behaviors in cephalopods. Motor patterning and chromatophore control is one such role – FMRFamide-related peptides modulate the expansion of chromatophores (pigment cells) that produce dynamic skin patterns in cuttlefish (pmc.ncbi.nlm.nih.gov). Experimental studies in Sepia officinalis showed that applying FMRFamide or related peptides can alter chromatophore muscle contraction, affecting color change and body patterning (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This indicates FMRFamide’s involvement in the neural control of camouflage and display behaviors (likely via neuromuscular modulation in the skin). More generally, FMRFamide acts within the cephalopod CNS as a neuromodulator of locomotor and sensory circuits. It is considered a “broadcast” neurotransmitter that can adjust the excitability of networks, shaping behaviors such as locomotion, feeding, or escape responses (as observed in other mollusks (pmc.ncbi.nlm.nih.gov)).

2. Cardio-Excretory and Peripheral Effects: FMRFamide’s discovery as a cardio-excitatory peptide highlights its role in modulating muscle tissues. In the clam heart, FMRFamide increases heartbeat frequency and contraction strength (www.frontiersin.org). In cuttlefish, FMRFamide-immunoreactive neurons innervate parts of the gut and blood vessels, suggesting roles in regulating visceral muscle contraction and possibly excretory organs. In one study, a novel RFamide peptide (GNLFRFamide, from a related gene) increased contraction frequency of the cuttlefish rectum at nanomolar concentrations (www.sciencedirect.com). The FMRFa gene’s peptides (like FMRFamide, FLRFamide) likely have similar myotropic effects on smooth muscles in the reproductive and digestive systems (pubmed.ncbi.nlm.nih.gov). This modulatory control ensures that physiological rhythms (heart rate, gut motility) can be adjusted by the nervous system.

3. Reproductive Function: One of the most well-documented functions of FMRFamide in cephalopods is in reproduction and egg-laying. S. officinalis uses FaRP neuropeptides to coordinate ovulation and egg casing production. Henry et al. (1999) purified FMRFamide and related peptides from female optic lobes and demonstrated their effect on oviduct contraction (pubmed.ncbi.nlm.nih.gov). The tetrapeptides FMRFamide and FLRFamide strongly stimulated oviduct muscle contractions, promoting egg transport, whereas the larger peptides FIRFamide and ALSGDAFLRFamide reduced contraction frequency and tone (pubmed.ncbi.nlm.nih.gov). This suggests a finely tuned balance: some FaRPs trigger muscular contraction to propel oocytes, while others relax the tract between egg releases. The same study found FMRFamide-positive nerve fibers innervating the accessory sex glands (nidamental glands) that secrete the egg capsule (pubmed.ncbi.nlm.nih.gov). In vitro, FMRFamide modulated contractions of the nidamental gland, likely inducing secretion of egg capsule materials during ovulation (pubmed.ncbi.nlm.nih.gov). These results show that FMRFa peptides play an integral role in synchronizing ovulation with egg encapsulation and laying in cuttlefish.

In octopuses, FMRFamide appears to have analogous reproductive roles. Octopus vulgaris expresses FMRFamide in neurons that innervate the optic gland (a neuroendocrine gland controlling sexual maturation) (pmc.ncbi.nlm.nih.gov). Di Cosmo et al. (2003) reported that FMRFamide signalling influences gonadal development and reproductive timing in octopus, possibly by modulating optic gland hormone release (pmc.ncbi.nlm.nih.gov). In Sepiella (Chinese cuttlefish), FMRFamide expression rises during sexual maturation, and experimental evidence suggests it promotes aspects of reproductive development (www.sciencedirect.com). Taken together, FMRFa neuropeptides serve as key neuroendocrine regulators of cephalopod reproduction – linking the nervous system to reproductive organ function and timing.

4. Neuroendocrine Regulation (Optic Gland): The cephalopod optic gland is functionally analogous to the vertebrate pituitary, releasing hormones that trigger sexual maturation and senescence. FMRFamide-like peptides have been found in neurons projecting to the optic gland in cuttlefish (pmc.ncbi.nlm.nih.gov) and squid, hinting at regulatory control. Early immunohistochemical work (Le Guez et al. 1988) showed FMRFamide-immunoreactive fibers densely innervating the Sepia optic gland (pmc.ncbi.nlm.nih.gov). This peptidergic innervation suggests FMRFamide could modulate the gland’s endocrine output. Indeed, applying FMRFamide in Octopus can alter optic gland activity and was linked to changes in reproductive hormone levels (pmc.ncbi.nlm.nih.gov). Thus, FMRFa peptides may act as neuroendocrine messengers, ensuring that environmental or neural cues appropriately influence hormone release for reproduction. This role fits into the broader reproductive function described above and highlights FMRFamide as a bridge between nervous and endocrine systems in cephalopods.

5. Immune System Modulation: Sepia FMRFamide is now recognized to also participate in the neuroimmune axis. A recent 2022 study demonstrated that FMRFamide has an immunoregulatory role during stress in cuttlefish (www.frontiersin.org) (www.frontiersin.org). When juvenile S. japonica were challenged with bacterial infection (Vibrio), FMRFa gene expression in neural tissues was significantly upregulated alongside nitric oxide synthase (NOS) expression (www.frontiersin.org). This co-expression led researchers to investigate FMRFamide’s effect on immune-related nitric oxide (NO) production. Strikingly, knockdown of the FMRFa precursor gene via RNA interference caused excessive NO production after immune challenge, whereas adding exogenous FMRFamide peptide suppressed NO levels (www.frontiersin.org). Whole-mount in situ hybridization showed FMRFa mRNA and NOS mRNA co-localized in certain tissues, suggesting direct interaction (www.frontiersin.org). Collectively, these results indicate that FMRFamide acts as a negative feedback regulator of inflammation, inhibiting NO synthesis to prevent overshooting cytotoxic immune responses (www.frontiersin.org). The proposed model is that during late-stage immune responses, neural FMRFamide is released to dampen macrophage or hemocyte activity, curbing nitric oxide-mediated damage (www.frontiersin.org). This discovery expands FMRFamide’s functional repertoire beyond the nervous system, identifying it as a component of cephalopod innate immune regulation (likely via neuroendocrine-immune signaling pathways). It also underscores cephalopods as “advanced” invertebrates with intricate neuroimmune communication (www.frontiersin.org).

Current Research Directions and Applications

FMRFa peptides in Sepia and other cephalopods remain an active research area, with recent studies focusing on receptor characterization and potential applications in aquaculture. Receptor Identification: In late 2023, Xie et al. cloned the first FMRFamide-specific GPCR from S. japonica, confirming the molecular target through which FMRFa neuropeptides exert many effects (www.sciencedirect.com). Similarly, the FaNaC ion channel gene was cloned in 2024, and its expression in reproductive organs hints at a role in mediating FMRFamide’s effects on gonadal maturation (pubmed.ncbi.nlm.nih.gov). Characterizing these receptors helps decipher the signal transduction pathways (e.g., which second messengers or ion currents are involved) and could reveal drug targets to modulate FMRFamide signaling.

Physiological Genomics: With the sequencing of cephalopod genomes, researchers have identified multiple FMRFamide gene variants. In Sepia officinalis, at least two distinct FaRP precursor genes exist (termed SOFaRP1 and SOFaRP2) (www.frontiersin.org). The second gene (SOFaRP2) was described in 2012 with a distinct expression pattern in the brain (www.frontiersin.org). The diversity of RFamide peptides from these genes (~75 different RFamide peptides across mollusks) and their spatial expression suggest specialized functions (www.frontiersin.org) (www.frontiersin.org). Ongoing work is examining how different RFamide peptides (e.g. the unique GNLFRFamide vs. FMRFamide) have differentiated roles, and how alternative splicing or gene duplication contributes to neural complexity in cephalopods (pmc.ncbi.nlm.nih.gov).

Aquaculture and Applied Research: Understanding FMRFa’s function has practical implications, especially for cephalopod aquaculture and biology. Cuttlefish are short-lived and semelparous (single reproductive cycle), so manipulating neuropeptide signals could influence reproduction and growth. The 2018 S. japonica study suggested that knowledge of FMRFamide regulation may aid in developing aquaculture techniques (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). For instance, if FMRFamide or its analogs can be used to synchronize or induce spawning and egg-laying, hatchery efficiency could improve. Likewise, intervening in FMRFamide signaling might modulate stress responses or immunity in captive cephalopods, improving survival. While these applications are still speculative, they stem from the recognized roles of FMRFamide in coordinating key physiological processes (reproduction, muscle contraction, immune balance). Additionally, FMRFamide is used as a research tool in neurobiology – as a known modulator, it’s applied to probe neural circuit function in mollusks. Its ability to activate FaNaC channels, for example, makes it useful for studies of ion channel gating and neuropharmacology (pubmed.ncbi.nlm.nih.gov).

Experts in neuropeptide biology consider FMRFamide and related FaRPs to be central regulators in molluscan physiology. They note that a single FMRFa precursor gene can influence an array of systems – “from chromatophore expansion and locomotion to reproduction and even immune defense” – by releasing multiple peptides that target different receptors (pmc.ncbi.nlm.nih.gov) (www.frontiersin.org). Such breadth of action is a hallmark of neuromodulators. Despite this pleiotropy, each role of FMRFamide is quite specific in context. In summary, the Sepia officinalis FMRFa gene encodes a multi-peptide neurohormone system that integrates neural, endocrine, and immune functions. Its peptides act as messengers that fine-tune muscular activity, developmental timing, and homeostatic responses, making FMRFamide a pivotal molecule for the physiology and behavior of cephalopods.

References: Recent key studies and reviews underpinning this annotation include: Henry et al., 1999 (Peptides) (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov); Di Cosmo et al., 2003 (pmc.ncbi.nlm.nih.gov); Loi & Tublitz, 1996/2006 on chromatophores (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov); Le Guez et al., 1988 on optic gland innervation (pmc.ncbi.nlm.nih.gov); Ying Li et al., 2018 (Molecules) on cuttlefish FMRFa gene characterization (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov); Zheng et al., 2022 (Front. Immunol.) on neuroimmune function (www.frontiersin.org) (www.frontiersin.org); and Xie/Li et al., 2024 (Neuropeptides) on FMRFamide receptors (www.sciencedirect.com), among others. These sources provide detailed experimental evidence of FMRFa’s structure, expression, and diverse functions across physiology. The consensus from authoritative reviews is that FMRFamide-related peptides are ubiquitous and versatile neuromodulators, underscoring the importance of the FMRFa gene in molluscan neurobiology (pmc.ncbi.nlm.nih.gov).

Citations

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  29. AnnotationURLCitation(end_index=12024, start_index=11896, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=neuroactive%20peptides%2C%20FMRFamide,16%2C7')
  30. AnnotationURLCitation(end_index=12447, start_index=12268, title='Frontiers | Diversity of the RFamide Peptide Family in Mollusks', type='url_citation', url='https://www.frontiersin.org/articles/10.3389/fendo.2014.00178/full#:~:text=Since%20the%20initial%20characterization%20of,related%20peptide%20gene%2C%20the')
  31. AnnotationURLCitation(end_index=12950, start_index=12791, title='Characterization of a novel LFRFamide neuropeptide in the cephalopod Sepia officinalis - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/abs/pii/S0196978109005129#:~:text=the%20peptide%20of%20m%2Fz%20752,9%20that%20is%20not')
  32. AnnotationURLCitation(end_index=13289, start_index=13104, title='Peptidergic control of egg-laying in the cephalopod Sepia officinalis: involvement of FMRFamide and FMRFamide-related peptides - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10499423/#:~:text=four%20immunoreactive%20fractions%20detected%20revealed,Indeed%2C%20FMRFa%20modulates%20the%20contractions')
  33. AnnotationURLCitation(end_index=13970, start_index=13785, title='Peptidergic control of egg-laying in the cephalopod Sepia officinalis: involvement of FMRFamide and FMRFamide-related peptides - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10499423/#:~:text=four%20immunoreactive%20fractions%20detected%20revealed,Indeed%2C%20FMRFa%20modulates%20the%20contractions')
  34. AnnotationURLCitation(end_index=14378, start_index=14193, title='Peptidergic control of egg-laying in the cephalopod Sepia officinalis: involvement of FMRFamide and FMRFamide-related peptides - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10499423/#:~:text=four%20immunoreactive%20fractions%20detected%20revealed,Indeed%2C%20FMRFa%20modulates%20the%20contractions')
  35. AnnotationURLCitation(end_index=14834, start_index=14667, title='Peptidergic control of egg-laying in the cephalopod Sepia officinalis: involvement of FMRFamide and FMRFamide-related peptides - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10499423/#:~:text=oviduct%3A%20the%20tetrapeptides%20FMRFa%20and,ovulation%20and%20egg%20capsule%20coating')
  36. AnnotationURLCitation(end_index=15143, start_index=14976, title='Peptidergic control of egg-laying in the cephalopod Sepia officinalis: involvement of FMRFamide and FMRFamide-related peptides - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10499423/#:~:text=oviduct%3A%20the%20tetrapeptides%20FMRFa%20and,ovulation%20and%20egg%20capsule%20coating')
  37. AnnotationURLCitation(end_index=15586, start_index=15490, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=,5.%20%5BDOI')
  38. AnnotationURLCitation(end_index=15869, start_index=15768, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=,Google%20Scholar')
  39. AnnotationURLCitation(end_index=16186, start_index=16043, title='FMRFamide G protein-coupled receptors (GPCR) in the cuttlefish Sepiella japonica: Identification, characterization and expression profile - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/abs/pii/S0143417924000908#:~:text=receptors%20,coupled%20receptor%20of')
  40. AnnotationURLCitation(end_index=16754, start_index=16658, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=,4.%20%5BDOI')
  41. AnnotationURLCitation(end_index=17029, start_index=16933, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=,4.%20%5BDOI')
  42. AnnotationURLCitation(end_index=17353, start_index=17252, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=,Google%20Scholar')
  43. AnnotationURLCitation(end_index=18074, start_index=17905, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=Neuropeptide%20Phe,PCR%29%2C%20which%20indicated')
  44. AnnotationURLCitation(end_index=18287, start_index=18075, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=additional%20FMRFamide%20could%20still%20furtherly,and%20other%20invertebrates%20and%20will')
  45. AnnotationURLCitation(end_index=18692, start_index=18487, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=detailed%20knowledge%20is%20still%20little,NOS%20mRNA%20was%20highly%20significantly')
  46. AnnotationURLCitation(end_index=19223, start_index=19009, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=appeared%20colocalization%2C%20suggesting%20that%20at,indeed%20inhibit%20NO%20production%20to')
  47. AnnotationURLCitation(end_index=19533, start_index=19353, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=that%20both%20were%20likely%20to,of%20the%20NO%20level%20in')
  48. AnnotationURLCitation(end_index=19933, start_index=19721, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=additional%20FMRFamide%20could%20still%20furtherly,and%20other%20invertebrates%20and%20will')
  49. AnnotationURLCitation(end_index=20319, start_index=20107, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=additional%20FMRFamide%20could%20still%20furtherly,and%20other%20invertebrates%20and%20will')
  50. AnnotationURLCitation(end_index=20836, start_index=20630, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=serve%20as%20feedback%20regulation%20at,understanding%20the%20NEIS%20of%20cephalopods')
  51. AnnotationURLCitation(end_index=21429, start_index=21270, title='FMRFamide G protein-coupled receptors (GPCR) in the cuttlefish Sepiella japonica: Identification, characterization and expression profile - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/abs/pii/S0143417924000908#:~:text=receptors%20,of%20SjFaGPCR%20was%20predicted%20using')
  52. AnnotationURLCitation(end_index=21744, start_index=21602, title='A Na+ channel receptor of FMRFamide in the cephalopod Sepiella japonica: Identification, characterisation, and expression profiling during different stages of gonadal development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38776655/#:~:text=Quantitative%20real,functions%20of%20SjFaNaC%20in%20cephalopods')
  53. AnnotationURLCitation(end_index=22303, start_index=22190, title='Frontiers | Diversity of the RFamide Peptide Family in Mollusks', type='url_citation', url='https://www.frontiersin.org/articles/10.3389/fendo.2014.00178/full#:~:text=FMRFamide,011')
  54. AnnotationURLCitation(end_index=22514, start_index=22401, title='Frontiers | Diversity of the RFamide Peptide Family in Mollusks', type='url_citation', url='https://www.frontiersin.org/articles/10.3389/fendo.2014.00178/full#:~:text=FMRFamide,011')
  55. AnnotationURLCitation(end_index=22835, start_index=22675, title='Frontiers | Diversity of the RFamide Peptide Family in Mollusks', type='url_citation', url='https://www.frontiersin.org/articles/10.3389/fendo.2014.00178/full#:~:text=peptides%20,display%20a%20complex%20spatiotemporal%20pattern')
  56. AnnotationURLCitation(end_index=23033, start_index=22836, title='Frontiers | Diversity of the RFamide Peptide Family in Mollusks', type='url_citation', url='https://www.frontiersin.org/articles/10.3389/fendo.2014.00178/full#:~:text=FLPs%20represent%20approximately%2075%20distinct,display%20a%20complex%20spatiotemporal%20pattern')
  57. AnnotationURLCitation(end_index=23379, start_index=23260, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=match%20at%20L273%20to%20multiple,7')
  58. AnnotationURLCitation(end_index=23984, start_index=23807, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=expression%20analysis%20indicated%20the%20highest,methods%20for%20this%20cuttlefish%20species')
  59. AnnotationURLCitation(end_index=24156, start_index=23985, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=neuropeptide%20evolution%20or%20may%20prove,methods%20for%20this%20cuttlefish%20species')
  60. AnnotationURLCitation(end_index=25031, start_index=24902, title='A Na+ channel receptor of FMRFamide in the cephalopod Sepiella japonica: Identification, characterisation, and expression profiling during different stages of gonadal development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38776655/#:~:text=FMRFamide%2C%20a%20member%20of%20the,The%20protein')
  61. AnnotationURLCitation(end_index=25494, start_index=25393, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=officinalis%20,16')
  62. AnnotationURLCitation(end_index=25707, start_index=25495, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=additional%20FMRFamide%20could%20still%20furtherly,and%20other%20invertebrates%20and%20will')
  63. AnnotationURLCitation(end_index=26497, start_index=26312, title='Peptidergic control of egg-laying in the cephalopod Sepia officinalis: involvement of FMRFamide and FMRFamide-related peptides - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10499423/#:~:text=four%20immunoreactive%20fractions%20detected%20revealed,Indeed%2C%20FMRFa%20modulates%20the%20contractions')
  64. AnnotationURLCitation(end_index=26665, start_index=26498, title='Peptidergic control of egg-laying in the cephalopod Sepia officinalis: involvement of FMRFamide and FMRFamide-related peptides - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10499423/#:~:text=oviduct%3A%20the%20tetrapeptides%20FMRFa%20and,ovulation%20and%20egg%20capsule%20coating')
  65. AnnotationURLCitation(end_index=26792, start_index=26691, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=,Google%20Scholar')
  66. AnnotationURLCitation(end_index=26938, start_index=26837, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=,Google%20Scholar')
  67. AnnotationURLCitation(end_index=27040, start_index=26939, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=,Google%20Scholar')
  68. AnnotationURLCitation(end_index=27188, start_index=27092, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=,4.%20%5BDOI')
  69. AnnotationURLCitation(end_index=27403, start_index=27267, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=9,indicated%20that%20SjFMRFamide%20was%20transcribed')
  70. AnnotationURLCitation(end_index=27580, start_index=27404, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=Results%20of%20phylogenetic%20relation%20analysis,for%20the%20development%20of%20aquaculture')
  71. AnnotationURLCitation(end_index=27859, start_index=27645, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=appeared%20colocalization%2C%20suggesting%20that%20at,indeed%20inhibit%20NO%20production%20to')
  72. AnnotationURLCitation(end_index=28072, start_index=27860, title='Frontiers | Inhibitory Effect of FMRFamide on NO Production During Immune Defense in Sepiella japonica', type='url_citation', url='https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.825634/full#:~:text=additional%20FMRFamide%20could%20still%20furtherly,and%20other%20invertebrates%20and%20will')
  73. AnnotationURLCitation(end_index=28320, start_index=28139, title='FMRFamide G protein-coupled receptors (GPCR) in the cuttlefish Sepiella japonica: Identification, characterization and expression profile - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/abs/pii/S0143417924000908#:~:text=FMRFamide%20%20is%20a%20ubiquitous,of%20SjFaGPCR%20was%20predicted%20using')
  74. AnnotationURLCitation(end_index=28790, start_index=28662, title='Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica) - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6017766/#:~:text=neuroactive%20peptides%2C%20FMRFamide,16%2C7')