Tachykinins amplify the action of capsaicin on central histaminergic neurons.

Substance P (SP), a product of the tachykinin 1 (Tac1) gene, is expressed in many hypothalamic neurons. Its wake-promoting potential could be mediated through histaminergic (HA) neurons of the tuberomamillary nucleus (TMN), where functional expression of neurokinin receptors (NKRs) waits to be characterized. As in the process of nociception in the peripheral nervous system (PNS) capsaicin-receptor (transient potential vanilloid 1: TRPV1) signalling is amplified by local release of histamine and SP, we tested the involvement of tachykinins in the capsaicin-induced long-lasting enhancement (LLEcaps) of HA neurons firing by investigating selective neurokinin receptor ligands in the hypothalamic mouse brain slice preparation using patch-clamp recordings in cell-attached mode combined with single-cell RT-PCR. We report that the majority of HA neurons respond to SP (EC50 3 nM), express the SP precursor tachykinin 1 (Tac1) gene and at least one of the neurokinin receptors. Responses to selective agonists of three known neurokinin receptors were sensitive to corresponding antagonists. LLEcaps was significantly impaired by the neurokinin receptor antagonists, indicating that in hypothalamus, as in the PNS, release of tachykinins downstream to TRPV1 activation is able to boost the release of histamine. The excitatory action of SP on histaminergic neurons adds another pathway to the noradrenergic and orexinergic ones to synergistically enhance cortical arousal. We show NK1R to play a prominent role on HA neurons and thus the control of wakefulness.

Novel Pituitary Actions of TAC4 Gene Products in Teleost.

Tachykinin 4 (TAC4) is the latest member of the tachykinin family involved in several physiological functions in mammals. However, little information is available about TAC4 in teleost. In the present study, we firstly isolated TAC4 and six neurokinin receptors (NKRs) from grass carp brain and pituitary. Sequence analysis showed that grass carp TAC4 could encode two mature peptides (namely hemokinin 1 (HK1) and hemokinin 2 (HK2)), in which HK2 retained the typical FXGLM motif in C-terminal of tachyinin, while HK1 contained a mutant VFGLM motif. The ligand-receptor selectivity showed that HK2 could activate all 6 NKRs but with the highest activity for the neurokinin receptor 2 (NK2R). Interestingly, HK1 displayed a very weak activation for each NKR isoform. In grass carp pituitary cells, HK2 could induce prolactin (PRL), somatolactin α (SLα), urotensin 1 (UTS1), neuromedin-B 1 (NMB1), cocaine- and amphetamine-regulated transcript 2 (CART2) mRNA expression mediated by NK2R and neurokinin receptor 3 (NK3R) via activation cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), phospholipase C (PLC)/inositol 1,4,5-triphosphate (IP3)/protein kinase C (PKC) and calcium2+ (Ca2+)/calmodulin (CaM)/calmodulin kinase-II (CaMK II) cascades. However, the corresponding stimulatory effects triggered by HK1 were found to be notably weaker. Furthermore, based on the structural base for HK1, our data suggested that a phenylalanine (F) to valine (V) substitution in the signature motif of HK1 might have contributed to its weak agonistic actions on NKRs and pituitary genes regulation.

Ligand-dependent internalization of Bombyx mori tachykinin-related peptide receptor is regulated by PKC, GRK5 and ß-arrestin2/BmKurtz.

Tachykinin signaling system is present in both vertebrates and invertebrates, and functions as neuromodulator responsible for the regulation of various physiological processes. In human, the internalization of G protein-coupled receptors has been extensively characterized; however, the insect GPCR internalization has been rarely investigated. Here, we constructed two expression vectors of Bombyx tachykinin-related peptide receptor (BmTKRPR) fused with Enhanced Green Fluorescent Protein (EGFP) at the C-terminal end for direct visualization of receptor expression, localization, and trafficking in cultured mammalian HEK293 and insect Sf21 cells. Our results demonstrated that agonist-activated BmTKRPR underwent rapid internalization in a dose-and time-dependent manner via a clathrin-dependent pathway in both HEK293 and Sf21 cells. Further investigation via RNAi or specific inhibitors, or co-immunoprecipitation demonstrated that agonist-induced BmTKRPR internalization was mediated by PKC, GRK5 and ß-arrestin2/BmKurtz. In addition, we also observed that most of the internalized BmTKRP receptors were recycled to the cell surface via early endosomes upon peptide ligand removal. Our study provides the first in-depth information on mechanisms underlying insect TKRP receptor internalization and perhaps aids in the interpretation of the signaling in the regulation of physiological processes.

A single-nucleotide polymorphism induced alternative splicing in Tacr3 involves in hypoxic-ischemic brain damage.

Single-nucleotide polymorphism (SNP) and Alternative splicing (AS) were found to be implicated in certain diseases, nevertheless, the contributions of mRNA SNPs and AS to pathogenesis in developing rat brains with hypoxic-ischemic encephalopathy (HIE) remained largely vague. Additionally, the disease associated with Tacr3 was normosmic congenital hypogonadotropic hypogonadism, while the relationship between HIE and Tacr3 remained largely elusive. The current study was designed to investigate the differentially expressed mRNAs and related SNPs as well as AS in neonatal rats subjected to HIE to identify if the exhibition of AS was associated with SNPs under pathological condition. Firstly, we used postnatal day 7 Sprague-Dawley rats to construct neonatal HIE model, and analyzed the expression profiles of SNP mRNA in hypoxic-ischemic (HI) and sham brains by using RNA sequencing. Then four genes, including Mdfic, Lpp, Bag3 and Tacr3, connecting with HIE and exhibiting SNPs and AS were identified by bioinformatics analysis. Moreover, combined with exonic splicing enhancer (ESE) and alternative splice site predictor (ASSP) analysis, we found that Tacr3 is associated specifically with HIE through 258547789 G > A SNP in inside the Alt First Exon and 258548573 G > A SNP in outside the Alt First Exon. Taken together, our study provides new evidence to understand the role of Tacr3 in HIE and it is possibly a potential target for the treatment of HIE in future clinic trial.

NKB signaling in the posterodorsal medial amygdala stimulates gonadotropin release in a kisspeptin-independent manner in female mice.

Neurokinin B (NKB) signaling is critical for reproduction in all studied species. The existing consensus is that NKB induces GnRH release via kisspeptin (Kiss1) stimulation in the arcuate nucleus. However, the stimulatory action of NKB is dependent on circulating estrogen (E2) levels, without which, NKB inhibits luteinizing hormone (LH) release. Importantly, the evidence supporting the kisspeptin-dependent role of NKB, derives from models of persistent hypogonadal state [e.g. Kiss1r knock-out (KO) mice], with reduced E2 levels. Here, we demonstrate that in the presence of E2, NKB signaling induces LH release in a kisspeptin-independent manner through the activation of NK3R (NKB receptor) neurons in the posterodorsal medial amygdala (MePD). Importantly, we show that chemogenetic activation of MePD Kiss1 neurons induces LH release, however, the stimulatory action of NKB in this area is Kiss1 neuron-independent. These results document the existence of two independent neuronal circuitries within the MePD that regulate reproductive function in females. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Characterization of a tachykinin signalling system in the bivalve mollusc Crassostrea gigas.

Although tachykinin-like neuropeptides have been identified in molluscs more than two decades ago, knowledge on their function and signalling has so far remained largely elusive. We developed a cell-based assay to address the functionality of the tachykinin G-protein coupled receptor (Cragi-TKR) in the oyster Crassostrea gigas. The oyster tachykinin neuropeptides that are derived from the tachykinin precursor gene Cragi-TK activate the Cragi-TKR in nanomolar concentrations. Receptor activation is sensitive to Ala-substitution of critical Cragi-TK amino acid residues. The Cragi-TKR gene is expressed in a variety of tissues, albeit at higher levels in the visceral ganglia (VG) of the nervous system. Fluctuations of Cragi-TKR expression is in line with a role for TK signalling in C. gigas reproduction. The expression level of the Cragi-TK gene in the VG depends on the nutritional status of the oyster, suggesting a role for TK signalling in the complex regulation of feeding in C. gigas.

Effects of Chronic Tobacco Smoking on the Distribution of Tachykinin Receptors in Rat Pial Arteries.

Pial arteries of different diameter were studied in intact rats and after 6-month modeling of chronic tobacco smoking in rats. Expression of tachykinin NK1 receptors in pial arteries was studied by biomicroscopy and immunohistochemical methods. Chronic tobacco smoking induced considerable reorganizations of the arterial bed. The intensity of changes depended on the diameter of vessels. In small pial vessels that directly participate in the blood supply to the brain, pronounced vasodilatation and enhanced expression of NK1 receptors in the endothelium mediating the effects of substance P were observed; the number of these vessels also increased. The intensity of the response to tobacco smoke components decreased with increasing vessel diameter.

Role of a tachykinin-related peptide and its receptor in modulating the olfactory sensitivity in the oriental fruit fly, Bactrocera dorsalis (Hendel).

Insect tachykinin-related peptide (TRP), an ortholog of tachykinin in vertebrates, has been linked with regulation of diverse physiological processes, such as olfactory perception, locomotion, aggression, lipid metabolism and myotropic activity. In this study, we investigated the function of TRP (BdTRP) and its receptor (BdTRPR) in an important agricultural pest, the oriental fruit fly Bactrocera dorsalis. BdTRPR is a typical G-protein coupled-receptor (GPCR), and it could be activated by the putative BdTRP mature peptides with the effective concentrations (EC50) at the nanomolar range when expressed in Chinese hamster ovary cells. Consistent with its role as a neuromodulator, expression of BdTRP was detected in the central nervous system (CNS) of B. dorsalis, specifically in the local interneurons with cell bodies lateral to the antennal lobe. BdTRPR was found in the CNS, midgut and hindgut, but interestingly also in the antennae. To investigate the role of BdTRP and BdTRPR in olfaction behavior, adult flies were subjected to RNA interference, which led to a reduction in the antennal electrophysiological response and sensitivity to ethyl acetate in the Y-tube assay. Taken together, we demonstrate the impact of TRP/TRPR signaling on the modulation of the olfactory sensitivity in B. dorsalis. The result improve our understanding of olfactory processing in this agriculturally important pest insect.

The expression of tachykinin receptors in the human lower esophageal sphincter.

Mammalian tachykinins are a family of neuropeptides which are potent modulators of smooth muscle function with a significant contractile effect on human smooth muscle preparations. Tachykinins act via three distinct G protein-coupled neurokinin (NK) receptors, NK1, NK2 and NK3, coded by the genes TACR1, TACR2 and TACR3 respectively. The purpose of this paper was to measure the mRNA and protein expression of these receptors and their isoforms in the clasp and sling fibers of the human lower esophageal sphincter complex and circular muscle from the adjacent distal esophagus and proximal stomach. We found differences in expression between the different receptors within these muscle types, but the rank order of the receptor expression did not differ between the different muscle types. The rank order of the mRNA expression was TACR2 (α isoform)>TACR2 (ß isoform)>TACR1 (short isoform)>TACR1 (long isoform)>TACR3. The rank order of the protein expression was NK2>NK1>NK3. This is the first report of the measurement of the transcript and protein expression of the tachykinin receptors and their isoforms in the muscles of the human lower esophageal sphincter complex. The results provide evidence that the tachykinin receptors could contribute to the regulation of the human lower esophageal sphincter, particularly the TACR2 α isoform which encodes the functional isoform of the tachykinin NK2 receptor was the most highly expressed of the tachykinin receptors in the muscles associated with the lower esophageal sphincter.

A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism.

CONTEXT: Delayed puberty (DP) is a common issue and, in the absence of an underlying condition, is typically self limited. Alhough DP seems to be heritable, no specific genetic cause for DP has yet been reported. In contrast, many genetic causes have been found for idiopathic hypogonadotropic hypogonadism (IHH), a rare disorder characterized by absent or stalled pubertal development. OBJECTIVE: The objective of this retrospective study, conducted at academic medical centers, was to determine whether variants in IHH genes contribute to the pathogenesis of DP. SUBJECTS AND OUTCOME MEASURES: Potentially pathogenic variants in IHH genes were identified in two cohorts: 1) DP family members of an IHH proband previously found to have a variant in an IHH gene, with unaffected family members serving as controls, and 2) DP individuals with no family history of IHH, with ethnically matched control subjects drawn from the Exome Aggregation Consortium. RESULTS: In pedigrees with an IHH proband, the proband's variant was shared by 53% (10/19) of DP family members vs 12% (4/33) of unaffected family members (P = .003). In DP subjects with no family history of IHH, 14% (8/56) had potentially pathogenic variants in IHH genes vs 5.6% (1 907/33 855) of controls (P = .01). Potentially pathogenic variants were found in multiple DP subjects for the genes IL17RD and TAC3. CONCLUSIONS: These findings suggest that variants in IHH genes can contribute to the pathogenesis of self-limited DP. Thus, at least in some cases, self-limited DP shares an underlying pathophysiology with IHH.

HGF expression induced by HIF-1α promote the proliferation and tube formation of endothelial progenitor cells.

Hypoxia-inducible factor-1α (HIF-1α) and hepatocyte growth factor (HGF) play important roles in postnatal neovascularization. However, the interaction of these two pathways is not fully understood. The present study utilized CoCl(2) treated-endothelial progenitor cells (EPCs) (EPCs exposure to CoCl(2) are under mimic hypoxia) to examine the expressions of HIF-1α and HGF and futher to assess whether or not the inhibitor (2-methoxyestradiol [2ME2]) of HIF-1α decrease the HGF expression. In addition, to investigate the effects of HGF on the proliferation and tube formation of EPCs under mimic hypoxia, EPCs were transfected with NK4 (HGF antagonist) plasmid and exposed to CoCl(2), then the proliferation of these EPCs was assayed by MTS and the tube formation capacity of these EPCs on Matrigel was detected. The analysis indicated that CoCl(2) treatment induced HIF-1α expression of EPCs, and futher promoted HGF expression. While after 2ME2 was used in CoCl(2) treated-EPCs, HGF expression was markedly inhibited compared with non-pretreated EPCs with 2ME2, which also showed that HGF expression in EPCs was mediated by HIF-1α. Further, the results showed that after EPCs were transfected with NK4 in spite of being exposed to CoCl(2), their proliferation activity and tube formation capacity were weakened, which in turn indicated that HGF could promote the proliferation and the tube formation of EPCs, and this process might be regulated by HIF-1α.

Expression of neurokinin B/NK3 receptor and kisspeptin/KISS1 receptor in human granulosa cells.

STUDY QUESTION: Are neurokinin B (NKB), NK3 receptor (NK3R), kisspeptin (KISS1) and kisspeptin receptor (KISS1R) expressed in human ovarian granulosa cells? SUMMARY ANSWER: The NKB/NK3R and kisspeptin/KISS1R systems are co-expressed and functionally active in ovarian granulosa cells. WHAT IS KNOWN ALREADY: The NKB/NK3R and KISS1/KISS1R systems are essential for reproduction. In addition to their well-recognized role in hypothalamic neurons, these peptide systems may contribute to the control of fertility by acting directly on the gonads, but such a direct gonadal role remains largely unknown. STUDY DESIGN, SIZE, DURATION: This study analyzed matched mural granulosa cells (MGCs) and cumulus cells (CCs) collected from preovulatory follicles of oocyte donors at the time of oocyte retrieval. PARTICIPANTS/MATERIALS, SETTING, METHODS: The samples were provided by 56 oocyte donor women undergoing ovarian stimulation treatment. Follicular fluid samples containing MGCs and cumulus-oocyte complexes were collected after transvaginal ultrasound-guided oocyte retrieval. RT-PCR, quantitative real-time PCR, immunocytochemistry and western blot were used to investigate the pattern of expression of the NKB/NK3R and KISS/KISS1R systems in MGCs and CCs. Intracellular free Ca(2+) levels, [Ca(2+)]i, in MGCs after exposure to NKB or KISS1, in the presence or not of tachykinin receptor antagonists, were also measured. MAIN OUTCOME AND THE ROLE OF CHANCE: NKB/NK3R and KISS1/KISS1R systems were expressed, at the mRNA and protein levels, in MGCs and CCs, with significantly higher expression in CCs. Kisspeptin increased the [Ca(2+)]i in the cytosol of human MGCs while exposure to NKB failed to induce any change in [Ca(2+)]i. However, the [Ca(2+)]i response to kisspeptin was reduced in the presence of NKB. The inhibitory effect of NKB was only partially mimicked by the NK3R agonist, senktide and marginally suppressed by the NK3R-selective antagonist SB 222200. Yet, a cocktail of antagonists selective for the NK1, NK2 and NK3 receptors blocked the effect of NKB. LIMITATIONS, REASONS FOR CAUTION: The granulosa and cumulus cells were obtained from oocyte donors undergoing ovarian stimulation, which in comparison with natural cycles, may have affected gene and protein expression in granulosa cells. WIDER IMPLICATIONS OF THE FINDINGS: Our data demonstrate that, in addition to their indispensable effects at the central nervous system, the NKB/NK3R and kisspeptin/KISS1R systems are co-expressed and are functionally active in non-neuronal reproductive cells of the female gonads, the ovarian granulosa cells. STUDY FUNDING/ COMPETING INTERESTS: This work was supported by grants from Ministerio de Economía y Competitividad (CTQ2011-25564 and BFI2011-25021) and Junta de Andalucía (P08-CVI-04185), Spain. J.G.-O., F.M.P., M.F.-S., N.P., A.C.-R., T.A.A., M.H., M.R., M.T.-S. and L.C. have nothing to declare.

Activation of BNGR-A24 by direct interaction with tachykinin-related peptides from the silkworm Bombyx mori leads to the Gq- and Gs-coupled signaling cascades.

Tachykinins constitute one of the largest peptide families in the animal kingdom and exert their diverse actions via G protein-coupled receptors (GPCRs). In this study, the Bombyx tachykinin-related peptides (TKRPs) were identified as specific endogenous ligands for the Bombyx neuropeptide GPCR A24 (BNGR-A24) and thus designated BNGR-A24 as BmTKRPR. Using both mammalian cell line HEK293 and insect cell line Sf21, further characterization demonstrated that BmTKRPR was activated, thus resulting in intracellular accumulation of cAMP, Ca(2+) mobilization, and ERK1/2 phosphorylation in a Gs and Gq inhibitor-sensitive manner. Moreover, quantitative reverse transcriptase polymerase chain reaction analysis and dsRNA-mediated knockdown experiments suggested a possible role for BmTKRPR in the regulation of feeding and growth. Our findings enhance the understanding of the Bombyx TKRP system in the regulation of fundamental physiological processes.

Direct regulation of gonadotropin release by neurokinin B in tilapia (Oreochromis niloticus).

Neurokinin B (NKB) was recently identified as a key regulator of reproduction in mammals and fish. Fish were found to possess a specific novel neurokinin termed NKF. To study the role of NKB/NKF in the regulation of fish reproduction and to investigate the role of NKB/NKF and their receptors in the piscine pituitary, we have identified the NKB/tachikinin 3 receptor (tac3r) system in tilapia. Bioinformatics and phylogenetic analyses have demonstrated that the tilapia holds 1 putative tac3 gene and 2 NKB receptor genes (tac3ra and tac3rb) that clustered with other piscine Tac3 and NKB receptor lineages. Furthermore, we found that in African cichlids, NKB peptides differ from other vertebrate NKBs in their C-terminal sequence, possessing isoleucine instead of valine as the X in the NKB FXGLM-NH2-terminal consensus sequence. Signal transduction analysis demonstrated that tilapia NKB (tiNKB), tiNKF, and human NKB activated both CRE-luc and SRE-luc transcriptional activity of both tilapia and human NKB receptors. Two hours after ip injection of tiNKB, the plasma levels of both FSH and LH were increased, whereas tiNKF was more effective in increasing LH levels. However, tiNKB was more effective than tiNKF in increasing both FSH and LH from tilapia pituitary dispersed cells. Using in situ hybridization and fluorescent immunohistochemistry, we have shown that LH cells possess tac3, tac3ra, and tac3rb mRNAs, whereas FSH cells possess mainly tac3rb and tac3ra and tac3 to a much lesser extent. These results suggest that the members of the NKB/tac3r system may serve as paracrine/autocrine regulators of gonadotropin release in fish pituitary.

Absence of GPR54 and TACR3 mutations in sporadic cases of idiopathic central precocious puberty.

BACKGROUND/AIMS: Kisspeptin (KISS1)/GPR54 (KISSR) signaling complex and neurokinin B (NKB)/NKB receptor (TACR3) signaling have been proposed as an integral part of the network coordinating GnRH release. GPR54 (KISS1R) and TACR3 gene mutations have been described in cases of idiopathic hypogonadotrophic hypogonadism, while limited data exist on gain-of-function mutation in GPR54 (KISS1R) gene causing idiopathic central precocious puberty (ICPP). No data on TACR3 mutations in ICPP have been described so far. The aim of this study was to elucidate the possible impact of GPR54 (KISS1R) and TACR3 mutations in ICPP. METHODS: PCR-amplified genomic DNA of 38 girls with ICPP was analyzed for GPR54 and TACR3 gene mutations. RESULTS: No GPR54 or TACR3 mutations were found. The A/G coding sequence single nucleotide polymorphism (SNP) on the GPR54 gene (dbSNP ID: rs10407968) was found in 2 patients with ICPP. CONCLUSION: Our data indicate that GPR54 and TACR3 gene mutations are not a frequent cause of ICPP. The identified A/G synonymous SNP (dbSNP ID: rs10407968) located in exon 1 of the gene is not likely to have a pathogenic role in exon splicing and therefore in the premature initiation of puberty.

Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease.

The tachykinins, exemplified by substance P, are one of the most intensively studied neuropeptide families. They comprise a series of structurally related peptides that derive from alternate processing of three Tac genes and are expressed throughout the nervous and immune systems. Tachykinins interact with three neurokinin G protein-coupled receptors. The signaling, trafficking, and regulation of neurokinin receptors have also been topics of intense study. Tachykinins participate in important physiological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems, including inflammation, nociception, smooth muscle contractility, epithelial secretion, and proliferation. They contribute to multiple diseases processes, including acute and chronic inflammation and pain, fibrosis, affective and addictive disorders, functional disorders of the intestine and urinary bladder, infection, and cancer. Neurokinin receptor antagonists are selective, potent, and show efficacy in models of disease. In clinical trials there is a singular success: neurokinin 1 receptor antagonists to treat nausea and vomiting. New information about the involvement of tachykinins in infection, fibrosis, and pruritus justifies further trials. A deeper understanding of disease mechanisms is required for the development of more predictive experimental models, and for the design and interpretation of clinical trials. Knowledge of neurokinin receptor structure, and the development of targeting strategies to disrupt disease-relevant subcellular signaling of neurokinin receptors, may refine the next generation of neurokinin receptor antagonists.

Tachykinin-expressing neurons control male-specific aggressive arousal in Drosophila.

Males of most species are more aggressive than females, but the neural mechanisms underlying this dimorphism are not clear. Here, we identify a neuron and a gene that control the higher level of aggression characteristic of Drosophila melanogaster males. Males, but not females, contain a small cluster of FruM(+) neurons that express the neuropeptide tachykinin (Tk). Activation and silencing of these neurons increased and decreased, respectively, intermale aggression without affecting male-female courtship behavior. Mutations in both Tk and a candidate receptor, Takr86C, suppressed the effect of neuronal activation, whereas overexpression of Tk potentiated it. Tk neuron activation overcame reduced aggressiveness caused by eliminating a variety of sensory or contextual cues, suggesting that it promotes aggressive arousal or motivation. Tachykinin/Substance P has been implicated in aggression in mammals, including humans. Thus, the higher aggressiveness of Drosophila males reflects the sexually dimorphic expression of a neuropeptide that controls agonistic behaviors across phylogeny.

Natalisin, a tachykinin-like signaling system, regulates sexual activity and fecundity in insects.

An arthropod-specific peptidergic system, the neuropeptide designated here as natalisin and its receptor, was identified and investigated in three holometabolous insect species: Drosophila melanogaster, Tribolium castaneum, and Bombyx mori. In all three species, natalisin expression was observed in 3-4 pairs of the brain neurons: the anterior dorso-lateral interneurons, inferior contralateral interneurons, and small pars intercerebralis neurons. In B. mori, natalisin also was expressed in two additional pairs of contralateral interneurons in the subesophageal ganglion. Natalisin-RNAi and the activation or silencing of the neural activities in the natalisin-specific cells in D. melanogaster induced significant defects in the mating behaviors of both males and females. Knockdown of natalisin expression in T. castaneum resulted in significant reduction in the fecundity. The similarity of the natalisin C-terminal motifs to those of vertebrate tachykinins and of tachykinin-related peptides in arthropods led us to identify the natalisin receptor. A G protein-coupled receptor, previously known as tachykinin receptor 86C (also known as the neurokinin K receptor of D. melanogaster), now has been recognized as a bona fide natalisin receptor. Taken together, the taxonomic distribution pattern of the natalisin gene and the phylogeny of the receptor suggest that natalisin is an ancestral sibling of tachykinin that evolved only in the arthropod lineage.

Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntington's disease.

Psychiatric symptoms such as depression and anxiety are important clinical features of Huntington's disease (HD). However, the underlying neurobiological substrate for the psychiatric features is not fully understood. In order to explore the biological origin of depression and anxiety in HD, we used a mouse model that expresses the human full-length mutant huntingtin, the BACHD mouse. We found that the BACHD mice displayed depressive- and anxiety-like features as early as at 2 months of age as assessed using the Porsolt forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM). BACHD mice subjected to chronic treatment with the anti-depressant sertraline were not different to vehicle-treated BACHD mice in the FST and EPM. The behavioral manifestations occurred in the absence of reduced hippocampal cell proliferation/neurogenesis or upregulation of the hypothalamic-pituitary-adrenal axis. However, alterations in anxiety- and depression-regulating genes were present in the hypothalamus of BACHD mice including reduced mRNA expression of neuropeptide Y, tachykinin receptor 3 and vesicular monoamine transporter type 2 as well as increased expression of cocaine and amphetamine regulated transcript. Interestingly, the orexin neuronal population in the hypothalamus was increased and showed cellular atrophy in old BACHD mice. Furthermore, inactivation of mutant huntingtin in a subset of the hypothalamic neurons prevented the development of the depressive features. Taken together, our data demonstrate that the BACHD mouse recapitulates clinical HD with early psychiatric aspects and point to the role of hypothalamic dysfunction in the development of depression and anxiety in the disease.

Induction of the neurokinin 1 receptor by TNFα in endometriotic tissue provides the potential for neurogenic control over endometriotic lesion growth.

CONTEXT: Endometriosis is characterized by the growth of ectopic endometrial tissue. Nerve fibers are frequently associated with ectopic lesions, and neurogenic inflammation may play a role in endometriosis. OBJECTIVE: The purpose of this study was to determine the presence of tachykinin receptors in endometriotic lesions and the role of TNFα on their expression. DESIGN: This study was an assessment of matching eutopic and ectopic endometrial tissue and peritoneal fluid from patients with endometriosis and an in vitro analysis of primary endometrial cells. SETTING: The setting was a university hospital. PATIENTS: Participants were premenopausal women undergoing laparoscopy. INTERVENTIONS: Endometriotic lesions were removed surgically. MAIN OUTCOME MEASURES: Tachykinin mRNA (TACR1/2) and protein (neurokinin 1 receptor [NK1R]) expression in both eutopic and ectopic endometrial tissue from patients with endometriosis and the correlation to peritoneal fluid TNFα were measured. Primary endometrial epithelial and stromal cells were assessed in vitro to determine the induction of TACR1/2 and NK1R expression after TNFα treatment. Cell viability of endometrial stromal cells after substance P exposure was also assessed. RESULTS: Expression of both TACR1 and TACR2 mRNA was significantly higher in the ectopic than in the eutopic tissue. Both TACR1 mRNA and NK1R protein expression was significantly correlated with peritoneal fluid TNFα, and in vitro studies confirmed that TNFα treatment induced both TACR1 mRNA and NK1R protein expression in endometrial stromal cells. In endometrial stromal cells, substance P treatment enhanced cell viability, which was inhibited by a specific NK1R antagonist. CONCLUSIONS: NK1R expression is induced in ectopic endometrial tissue by peritoneal TNFα. Induction of NK1R expression may permit endometriotic lesion maintenance via exposure to substance P.