The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross-reactivity with antibodies raised against bovine neuropeptide FF (NPFF). 26RFa and its N-terminally extended form glutamine RF-amide peptide (QRFP) have been identified as cognate ligands of the former orphan receptor GPR103, now renamed glutamine RF-amide peptide receptor (QRFP receptor). The 26RFa/QRFP precursor has been characterized in various mammalian and non-mammalian species. In the brain of mammals, including humans, 26RFa/QRFP mRNA is almost exclusively expressed in hypothalamic nuclei. The 26RFa/QRFP transcript is also present in various organs especially in endocrine glands. While humans express only one QRFP receptor, two isoforms are present in rodents. The QRFP receptor genes are widely expressed in the CNS and in peripheral tissues, notably in bone, heart, kidney, pancreas and testis. Structure-activity relationship studies have led to the identification of low MW peptidergic agonists and antagonists of QRFP receptor. Concurrently, several selective non-peptidic antagonists have been designed from high-throughput screening hit optimization. Consistent with the widespread distribution of QRFP receptor mRNA and 26RFa binding sites, 26RFa/QRFP exerts a large range of biological activities, notably in the control of energy homeostasis, bone formation and nociception that are mediated by QRFP receptor or NPFF2. The present report reviews the current knowledge concerning the 26RFa/QRFP-QRFP receptor system and discusses the potential use of selective QRFP receptor ligands for therapeutic applications.

Mast cell activation releases the mediators associated with type I allergy. As such, the study of mast cell activation is critical for understanding the allergic reaction, and for developing methods to control it. Importantly, another ligand receptor pair (compound 48/80 and MRGPRX2) that activates mast cells in addition to allergen-IgE-FcεRI has been identified. As mast cells mature in tissue from hematopoietic stem cells, their physiology and pathophysiology is difficult to study. Mast cell lines and mast cells cultured from stem cells are often studied instead of tissue mast cells. There has been some progress in the description of the mechanism of the activation of mast cells, substances limiting mast cell activation and in the catalogue of proteases that mast cells express. Basophil granulocytes express FcεRI, bind IgE and respond to allergen crosslinking in a very similar fashion to mast cells. In the recent literature, basophils were mistakenly described as antigen-presenting cells; this has convincingly been disputed in a number of subsequent publications. Their function in physiology and pathophysiology is not known, but they are frequently used to document allergic sensitisation in the basophil activation test. Significant progress has been made in documenting the relevance of basophil activation as a second-line test in allergy diagnosis. Basophil reactivity and sensitivity may reflect symptom severity and allergen threshold, and are used to document and monitor allergy. The physiology and pathophysiology of allergic effector cells remain an important area of research.

Juvenile hormones (JH) are highly pleiotropic insect hormones essential for post-embryonic development. The circulating JH titer in the hemolymph of insects is influenced by enzymatic degradation, binding to JH carrier proteins, uptake and storage in target organs, but evidently also by rates of production at its site of synthesis, the corpora allata (CA). The multiple processes in which JH is involved alongside the critical significance of JH in insect development emphasize the importance for elucidating the control of JH production. Production of JH in CA cells is regulated by different factors: by neurotransmitters, such as dopamine and glutamate, but also by allatoregulatory neuropeptides originating from the brain and axonally transported to the CA where they bind to their G protein-coupled receptors (GPCRs). Different classes of allatoregulatory peptides exist which have other functions aside from acting as influencers of JH production. These pleiotropic neuropeptides regulate different processes in different insect orders. In this mini-review, we will give an overview of allatotropins and allatostatins, and their recently characterized GPCRs with a view to better understand their modes of action and different action sites.

We analyzed possible mechanisms for the influence of the \"wakening hormone\" orexin on spatial learning acting via changes in the functioning of the hippocampus and connected structures. The literature data point out that, firstly, orexin can directly potentiate excitation of neurons in different hippocampal areas by acting on Gq/11-protein-coupled postsynaptic OX1 and OX2 receptors. Due to facilitation of induction of the long-term potentiation of excitatory transmission at each stage of trisynaptic pathway through the hippocampus, orexin can promote transduction of information through this structure and formation of neural representations of object-place associations. Secondly, orexin can increase the release of acetylcholine, GABA and glutamate in the hippocampus by enhancing activity of neurons in the medial septum that have OX1 and OX2 receptors. This could lead to changes in intensity and frequency of the hippocampal theta rhythm. Thirdly, orexin can influence the functioning of reinforcing networks that include neurons of the hippocampus, prefrontal cortex, amygdala, ventral striatum, and ventral tegmental area by direct modulation of their activity through OX receptors. By enhancing the activity of dopaminergic neurons and increasing dopamine release, orexin can improve the functioning of reinforcing networks and facilitate spatial learning.

Neuropeptides and their G protein-coupled receptors (GPCRs) have an early evolutionary origin and are already abundant in basal animals with primitive nervous systems such as cnidarians (Hydra, jellyfishes, corals, and sea anemones). Most animals emerging after the Cnidaria belong to two evolutionary lineages, the Protostomia (to which the majority of invertebrates belong) and Deuterostomia (to which some minor groups of invertebrates, and all vertebrates belong). These two lineages split about 700 million years (Myr) ago. Many mammalian neuropeptide GPCRs have orthologues in the Protostomia and this is also true for some of the mammalian neuropeptides. Examples are oxytocin/vasopressin, GnRH, gastrin/CCK, and neuropeptide Y and their GPCRs. These results implicate that protostomes (for example insects and nematodes) can be used as models to study the biology of neuropeptide signaling.

Drug discovery is an iterative process with high risks and low chance of success. New genomics technologies allow veterinary medicine and agrochemical companies to validate and functionally screen new receptor-based targets, including neuropeptide G-protein coupled receptors, which were previously not amenable to high throughput screening. However this is just the first step in a long process to translate a mechanistic assay hit into a drug on the market. In addition to effectively eradicating pests on crops and parasites on their host, the molecules must also be safe, cheap to synthesise, formulatable and patentable. This is a costly process in which early attrition of unsuitable molecules is key to any successful program. Although first principle discovery is risky the ultimate benefits are considerable and future genomics resources will help to generate higher quality hits to strengthen the discovery pipeline.

BACKGROUND: The orexin neuropeptide system plays a central role in maintaining arousal and wakefulness. It has been demonstrated that small molecule antagonists to the orexin receptors promote sleep in preclinical species and in patients with insomnia.
METHODS: This review provides a summary of published patent applications claiming novel orexin antagonists from 2006 to mid-2009, covering both selective and dual orexin receptor antagonists.
RESULTS: Readers will gain an overview of orexin biology focusing on genetic and pharmacological validation of this target for treating sleep disorders. Additionally, this review discusses the importance of receptor subtype selectivity and the potential role of subtype selective and dual orexin antagonists in treating psychiatric illnesses beyond insomnia. This review identifies companies that are significant contributors to the patent literature claiming novel orexin receptor antagonists.
CONCLUSIONS: The study of the orexin system has emerged as one of the key new fields of investigation in neuroscience. The demonstration of clinical proof-of-concept for the treatment of primary insomnia by Actelion in early 2007 has spurred significant interest in this field and competition has markedly increased since 2006.

An unexpected and fascinating aspect of the neuropeptides orexins has recently emerged when it was shown that orexins acting at orexin receptors OX1R or OX2R induce dramatic apoptosis resulting in massive reduction in cell growth in various cancer cell lines. This mini-review will provide the reader with recent findings related to the proapoptotic actions of orexins and the entirely novel mechanism whereby the seven membrane-spanning G-protein-coupled receptor (GPCR) OX1R triggers apoptosis. Recent data show that orexins induce tyrosine phosphorylation of the tyrosine-based motifs - immunoreceptor tyrosine-based inhibitory motif and immunoreceptor tyrosine-based switch motif - in OX1R. These phosphorylations result in the recruitment and activation of the phosphotyrosine phosphatase SHP-2 and subsequent cytochrome c-mediated mitochondrial apoptosis. Finally, this mini-review will also speculate on: (1) the potential importance of tyrosine-based motifs in the large family of GPCRs; (2) the interest of orexin receptors as therapeutic targets in cancer therapy; (3) the possible role of orexin receptor-mediated apoptosis in physiology and pathophysiology in the brain (neurodevelopment, neurodegenerative diseases) and in the periphery.

Narcolepsy is a chronic sleep disorder that affects human beings and animals. Up to 17 breeds of dogs are affected sporadically, and familial forms occur in dobermanns, labrador retrievers and dachshunds. These dogs display characteristics strikingly similar to those of human narcolepsy, including cataplexy (a sudden loss of muscle tone in response to emotional stimulation) and a shorter sleep latency. It has recently been shown that the aetiology of both the familial form (receptor null mutation) and the sporadic form (loss of ligand production) of canine narcolepsy is associated with a deficit in hypocretin/orexin neurotransmission. Hypocretin deficiency can be detected by the measurement of hypocretin-1 in cerebrospinal fluid, and this could be used to diagnose hypocretin ligand deficient cases in clinical practice. Narcolepsy is neither progressive nor life-threatening, but the clinical signs persist throughout life, and lifelong treatment and care are required. This article reviews the recent progress in narcolepsy research in dogs, and describes the diagnosis and treatment of the disease.

The open field is a very popular animal model of anxiety-like behavior. An overview of the literature on the action elicited by effective or putative anxiolytics in animal subjected to this procedure indicates that classical treatments such as benzodiazepine receptor full agonists or 5-HT(1A) receptor full or partial agonists elicit an anxiolytic-like effect in this procedure in most cases (approximately 2/3). However, compounds (triazolobenzodiazepines such as adinazolam and alprazolam, selective serotonin reuptake inhibitors) that have a different spectrum of therapeutic efficacy in anxiety disorders such as panic attacks, generalized anxiety disorder or obsessive-compulsive disorder were poorly effective as anxiolytics in the open field test, suggesting that this paradigm may not model features of anxiety disorders. The procedure is also relevant for the study of compounds endowed with anxiogenic effects, as such effects were detected after treatments with benzodiazepine receptor inverse agonists or with corticotropin releasing factor (CRF) receptor agonists.