Displaying publications 1 - 20 of 55 in total

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  1. Changes in Knee Laxity and Relaxin Receptor Isoforms Expression (RXFP1/RXFP2) in the Knee throughout Estrous Cycle Phases in Rodents
    Dehghan F, Soori R, Dehghan P, Gholami K, Muniandy S, Azarbayjani MA, et al.
    PLoS One, 2016;11(8):e0160984.
    PMID: 27513858 DOI: 10.1371/journal.pone.0160984
    The changes in knee laxity and relaxin receptor expression at different phases of rodent estrous cycle are not known. Here, changes in the parameter were investigated in rats at different phases of the estrous cycle. Estrous cycle phases of intact female rats were determined by cytological examination of the vaginal smear. Following phase identification, blood was collected for serum hormone analyses. Knee passive range of motion (ROM) was determined by using a digital miniature goniometer. The animals were then sacrificed and patellar tendon, collateral ligaments and hamstring muscles were harvested for relaxin/insulin-like family peptide receptor 1 and 2 (RXFP1/RXFP2) analyses. Knee passive ROM was the highest at proestrus followed by diestrus and the lowest at estrus. Estrogen level was the highest at proestrus while progesterone and relaxin levels were the highest at diestrus. A strong correlation was observed between relaxin and progesterone levels. At proestrus, expression of RXFP1 and RXFP2 proteins and mRNAs were the highest at proestrus followed by diestrus and estrus. The finding shows that higher level of progesterone and relaxin in diestrus might be responsible for higher laxity of knee joint in rats.
    Matched MeSH terms: Receptors, G-Protein-Coupled
  2. Inhibitory effects of xanthones on platelet activating factor receptor binding in vitro
    Jantan I, Juriyati J, Warif NA
    J Ethnopharmacol, 2001 May;75(2-3):287-90.
    PMID: 11297865
    Nine naturally occurring xanthones were investigated for their platelet activating factor (PAF) receptor binding inhibitory effects using rabbit platelets. 2-(3-methylbut-2-enyl)-1,3,5-trihydoxyxanthone, macluraxanthone, 1,3,5-trihydroxy-6,6'-dimethylpyrano(2',3':6,7)-4-(1,1-dimethylprop-2-enyl)xanthone, 6-deoxyjacareubin and 2-(3-methylbut-2-enyl)-1,3,5,6-terahydroxyxanthone showed strong inhibition with IC50 values of 4.8, 11.0, 21.0, 29.0 and 44.0 microM, respectively. The prenyl group at C-2, the dimethylprop-2-enyl group at C-4 and the hydroxyl group at C-5 are all beneficial to the binding of xanthones to the PAF receptor. The results revealed that xanthones can represent a new class of natural PAF receptor antagonists.
    Matched MeSH terms: Receptors, G-Protein-Coupled*
  3. Fulltext Inhibitory action of gonadotropin-inhibitory hormone on the signaling pathways induced by kisspeptin and vasoactive intestinal polypeptide in GnRH neuronal cell line, GT1-7
    Son YL, Ubuka T, Soga T, Yamamoto K, Bentley GE, Tsutsui K
    FASEB J, 2016 06;30(6):2198-210.
    PMID: 26929433 DOI: 10.1096/fj.201500055
    Gonadotropin-inhibitory hormone (GnIH) acts as a negative regulator of reproduction by acting on gonadotropes and gonadotropin-releasing hormone (GnRH) neurons. Despite its functional significance, the molecular mechanism of GnIH action in the target cells has not been fully elucidated. To expand our previous study on GnIH actions in gonadotropes, we investigated the potential signal transduction pathway that conveys the inhibitory action of GnIH in GnRH neurons by using the GnRH neuronal cell line, GT1-7. We examined whether GnIH inhibits the action of kisspeptin and vasoactive intestinal polypeptide (VIP), positive regulators of GnRH neurons. Although GnIH significantly suppressed the stimulatory effect of kisspeptin on GnRH release in hypothalamic culture, GnIH had no inhibitory effect on kisspeptin stimulation of serum response element and nuclear factor of activated T-cell response element activities and ERK phosphorylation, indicating that GnIH may not directly inhibit kisspeptin signaling in GnRH neurons. On the contrary, GnIH effectively eliminated the stimulatory effect of VIP on p38 and ERK phosphorylation, c-Fos mRNA expression, and GnRH release. The use of pharmacological modulators strongly demonstrated the specific inhibitory action of GnIH on the adenylate cyclase/cAMP/protein kinase A pathway, suggesting a common inhibitory mechanism of GnIH action in GnRH neurons and gonadotropes.-Son, Y. L., Ubuka, T., Soga, T., Yamamoto, K., Bentley, G. E., Tsutsui, K. Inhibitory action of gonadotropin-inhibitory hormone on the signaling pathways induced by kisspeptin and vasoactive intestinal polypeptide in GnRH neuronal cell line, GT1-7.
    Matched MeSH terms: Receptors, G-Protein-Coupled/genetics; Receptors, G-Protein-Coupled/metabolism
  4. Beta amino acid-modified and fluorescently labelled kisspeptin analogues with potent KISS1R activity
    Camerino MA, Liu M, Moriya S, Kitahashi T, Mahgoub A, Mountford SJ, et al.
    J. Pept. Sci., 2016 Jun;22(6):406-14.
    PMID: 27282137 DOI: 10.1002/psc.2883
    Kisspeptin analogues with improved metabolic stability may represent important ligands in the study of the kisspeptin/KISS1R system and have therapeutic potential. In this paper we assess the activity of known and novel kisspeptin analogues utilising a dual luciferase reporter assay in KISS1R-transfected HEK293T cells. In general terms the results reflect the outcomes of other assay formats and a number of potent agonists were identified among the analogues, including β(2) -hTyr-modified and fluorescently labelled forms. We also showed, by assaying kisspeptin in the presence of protease inhibitors, that proteolysis of kisspeptin activity within the reporter assay itself may diminish the agonist outputs. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism*; Receptors, G-Protein-Coupled/chemistry
  5. Quantitative autoradiographic studies of relaxin binding in rat atria, uterus and cerebral cortex: characterization and effects of oestrogen treatment
    Tan YY, Wade JD, Tregear GW, Summers RJ
    Br J Pharmacol, 1999 May;127(1):91-8.
    PMID: 10369460
    The binding characteristics of the relaxin receptor in rat atria, uterus and cortex were studied using a [33P]-labelled human gene 2 relaxin (B33) and quantitative receptor autoradiography. The binding kinetics of [33P]-human gene 2 relaxin (B33) were investigated in slide-mounted rat atrial sections. The binding achieved equilibrium after 60 min incubation at room temperature (23+/-1 degrees C) and dissociated slowly. The association and dissociation rate constants were 4.31+/-0.34x10(8) M(-1) x min(-1) and 1.55+/-0.38x10(-3) min(-1) respectively. Thus, the kinetic dissociation constant was 3.46+/-0.59 pM. Binding was saturable to a single population of non-interacting sites throughout atria, in uterine myometrium and the 5th layer of cerebral cortex. The binding affinities (pK(D)) of [33P]-human gene 2 relaxin (B33) were 8.92+/-0.09 in atrial myocardium and 8.79+/-0.04 in cerebral cortex of male rats, and 8.79+/-0.10 in uterine myometrium. Receptor densities in the cerebral cortex and atria were higher than in uterine myometrium, indicating that relaxin also has important roles in non-reproductive tissues. In male rats, treatment with 17beta-oestradiol (20 microg in 0.1 ml sesame oil s.c., 18-24 h) significantly decreased the density of relaxin receptors in atria and cerebral cortex. Identical treatment in female rats had no significant effect in atria and cerebral cortex, but it significantly increased the density of relaxin receptors in uterine myometrium. Relaxin binding was competitively displaced by porcine and rat native relaxins. Porcine native relaxin binds to the relaxin receptor in male rat atria (8.90+/-0.02), and cerebral cortex (8.90+/-0.03) and uterine myometrium (8.89+/-0.03) with affinities not significantly different from human gene 2 (B33) relaxin. Nevertheless, rat relaxin binds to the receptors with affinities (8.35+/-0.09 in atria, 8.22+/-0.07 in cerebral cortex and 8.48+/-0.06 in uterine myometrium) significantly less than human gene 2 (B33) and porcine relaxins. Quantitative receptor autoradiography is the method of choice for measurement of affinities and densities of relaxin receptor in atria, uterine myometrium and cerebral cortex. High densities were found in all these tissues. 17beta-oestradiol treatment produced complex effects where it increased the densities of relaxin receptors in uterus but decreased those in atria and cerebral cortex of the male rats, and had no effect on the atria and cerebral cortex of the female rats.
    Matched MeSH terms: Receptors, G-Protein-Coupled
  6. Comparison of relaxin receptors in rat isolated atria and uterus by use of synthetic and native relaxin analogues
    Tan YY, Wade JD, Tregear GW, Summers RJ
    Br J Pharmacol, 1998 Feb;123(4):762-70.
    PMID: 9517397
    1. The receptors for relaxin in the rat atria and uterus were investigated and compared by use of a series of synthetic and native relaxin analogues. The assays used were the positive chronotropic and inotropic effects in rat spontaneously beating, isolated right atrium and electrically driven left atrium and the relaxation of K+ precontracted uterine smooth muscle. 2. Relaxin analogues with an intact A- and B-chain were active in producing powerful chronotropic and inotropic effects in the rat isolated atria at nanomolar concentrations. Single-chain analogues and structural homologues of relaxin such as human insulin and sheep insulin-like growth factor I had no agonist action and did not antagonize the effect of the B29 form of human gene 2 relaxin. 3. Shortening the B-chain carboxyl terminal of human gene 1 (B2-29) relaxin to B2-26 reduced the activity of the peptide and removal of another 2 amino acid residues (B2-24) abolished the activity. This suggests that the B-chain length may be important for determination of the activity of relaxin. More detailed studies are needed to determine the effect of progressive amino acid removal on the structure and the bioactivity of relaxin. 4. Porcine prorelaxin was as active as porcine relaxin on a molar basis, suggesting that the presence of the intact C-peptide did not affect the binding of the prorelaxin to the receptor to produce functional responses. 5. Relaxin caused relaxation of uterine longitudinal and circular smooth muscle precontracted with 40 mM K+. The pEC50 values for human gene 2 and porcine relaxins were lower than those in the atrial assay, but rat relaxin had similar pEC50 values in both atrial and uterine assays. Rat relaxin was significantly less potent than either human gene 2 or porcine relaxin in the atrial assay, but in the uterine assay they were equipotent. The results suggest that the relaxin receptor or the signalling pathway in rat atria may differ from that in the uterus.
    Matched MeSH terms: Receptors, G-Protein-Coupled
  7. Fulltext Inhibitory effects of phylligenin and quebrachitol isolated from Mitrephora vulpina on platelet activating factor receptor binding and platelet aggregation
    Moharam BA, Jantan I, Jalil J, Shaari K
    Molecules, 2010 Nov 03;15(11):7840-8.
    PMID: 21060292 DOI: 10.3390/molecules15117840
    Phylligenine, together with quebrachitol, stigmasterol and two aporphine alkaloids--oxoputerine and liriodenine--were isolated from the twigs of Mitrephora vulpina C.E.C. Fisch. They were evaluated for their ability to inhibit platelet activating factor (PAF) receptor binding to rabbit platelets using 3H-PAF as a ligand and their antiplatelet aggregation effect in human whole blood induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP). Of all the compounds tested, phylligenin and quebrachitol exhibited potent and concentration-dependent inhibitory effects on PAF receptor binding, with IC(50) values of 13.1 and 42.2 µM, respectively. The IC(50) value of phylligenin was comparable to that of cedrol (10.2 µM), a potent PAF antagonist. Phylligenin also showed strong dose-dependent inhibitory activity on platelet aggregation induced by AA and ADP.
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism*
  8. Fulltext Bitter receptor gene (TAS2R38) P49A genotypes and their associations with aversion to vegetables and sweet/fat foods in Malaysian subjects
    Ooi SX, Lee PL, Law HY, Say YH
    Asia Pac J Clin Nutr, 2010;19(4):491-8.
    PMID: 21147709
    Recently, the bitter receptor gene (TAS2R38) was identified to be responsible for phenylthiocarbamide (PTC) bitter sensitivity. Its two predominant haplotypes at three Single Nucleotide Polymorphisms (SNPs) are found to be definitive for the PTC status, which the ProAlaVal and AlaValIle haplotypes are associated with tasters and non-tasters, respectively. TAS2R38 haplotypes have been reported to influence food preferences (like cruciferous vegetables and fat foods) and cardiovascular disease risk factors. We examined, in 215 Malaysian subjects (100 males, 115 females), the association of the P49A SNP of TAS2R38 with anthropometric measurements and aversion to a list of 36 vegetables, 4 soy products, green tea and 37 sweet/fat foods. The subjects were successfully genotyped as 110 PA, 81 PP and 24 AA (with the A49 allelic frequency of 0.37), by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Ethnicity (Malay, Chinese or Indian), but not gender, was associated with the P49A TAS2R38 genotypes (p<0.001). However, no significant differences in terms of Body Mass Index, Total Body Fat, waist circumference and Waist-Hip Ratio were found between the genotypes (p<0.05). Only aversions to green tea, mayonnaise and whipped cream, but not soy products, vegetables, and other sweet/fat foods, were associated with the P49A genotypes (p<0.05). Therefore, the P49A SNP of the bitter receptor gene TAS2R38 could not serve as a predictor of anthropometric measurements and aversion to vegetables or sweet/fat foods in the sampled Malaysian subjects, and this suggests the existence of other possible factors influencing food selection among Malaysians.
    Matched MeSH terms: Receptors, G-Protein-Coupled/genetics*
  9. Fulltext Testosterone reduces knee passive range of motion and expression of relaxin receptor isoforms via 5α-dihydrotestosterone and androgen receptor binding
    Dehghan F, Muniandy S, Yusof A, Salleh N
    Int J Mol Sci, 2014;15(3):4619-34.
    PMID: 24642882 DOI: 10.3390/ijms15034619
    Ovarian steroids such as estrogen and progesterone have been reported to influence knee laxity. The effect of testosterone, however, remains unknown. This study investigated the effect of testosterone on the knee range of motion (ROM) and the molecular mechanisms that might involve changes in the expression of relaxin receptor isoforms, Rxfp1 and Rxfp2 in the patella tendon and lateral collateral ligament of the female rat knee. Ovariectomized adult female Wistar rats received three days treatment with peanut oil (control), testosterone (125 and 250 μg/kg) and testosterone (125 and 250 μg/kg) plus flutamide, an androgen receptor blocker or finasteride, a 5α-reductase inhibitor. Duplicate groups received similar treatment however in the presence of relaxin (25 ng/kg). A day after the last drug injection, knee passive ROM was measured by using a digital miniature goniometer. Both tendon and ligament were harvested and then analysed for protein and mRNA expression for Rxfp1 and Rxfp2 respectively. Knee passive ROM, Rxfp1 and Rxfp2 expression were significantly reduced following treatment with testosterone. Flutamide or finasteride administration antagonized the testosterone effect. Concomitant administration of testosterone and relaxin did not result in a significant change in knee ROM as compared to testosterone only treatment; however this was significantly increased following flutamide or finasteride addition. Testosterone effect on knee passive ROM is likely mediated via dihydro-testosterone (DHT), and involves downregulation of Rxfp1 and Rxfp2 expression, which may provide the mechanism underlying testosterone-induced decrease in female knee laxity.
    Matched MeSH terms: Receptors, G-Protein-Coupled/genetics; Receptors, G-Protein-Coupled/metabolism*
  10. Estrogen receptor (ER)-α, β and progesterone receptor (PR) mediates changes in relaxin receptor (RXFP1 and RXFP2) expression and passive range of motion of rats' knee
    Dehghan F, Yusof A, Muniandy S, Salleh N
    Environ Toxicol Pharmacol, 2015 Nov;40(3):785-91.
    PMID: 26447688 DOI: 10.1016/j.etap.2015.09.004
    The high risk of knee injuries in female may be associated with sex-steroid hormone fluctuations during the menstrual cycle by its effect on ligaments and tendons stiffness. This study examined changes in knee range of motion in presence of estrogen and progesterone and investigated the interaction of their antagonists to relaxin receptors.
    Matched MeSH terms: Receptors, G-Protein-Coupled/genetics*; Receptors, G-Protein-Coupled/metabolism
  11. Fulltext Sex-steroid regulation of relaxin receptor isoforms (RXFP1 & RXFP2) expression in the patellar tendon and lateral collateral ligament of female WKY rats
    Dehghan F, Muniandy S, Yusof A, Salleh N
    Int J Med Sci, 2014;11(2):180-91.
    PMID: 24465164 DOI: 10.7150/ijms.6283
    The incidence of non-contact knee injury was found higher in female than in male and is related to the phases of the menstrual cycle. This raised the possibility that female sex-steroids are involved in the mechanism underlying this injury via affecting the expression of the receptors for relaxin, a peptide hormone known to modulate ligament laxity. Therefore, this study aims to investigate the effect of sex-steroids on relaxin receptor isoforms (RXFP1 & RXFP2) expression in the ligaments and tendons of the knee.

    METHODS: Ovariectomized adult female WKY rats were treated with different doses of estrogen (0.2, 2, 20 μg/kg), progesterone (4mg) and testosterone (125 & 250μg/kg) for three consecutive days. At the end of the treatment, the animals were sacrificed and the patellar tendon and lateral collateral ligament were harvested for mRNA and protein expression analyses by Real Time PCR and Western blotting respectively.

    RESULTS: RXFP1, the main isoform expressed in these knee structures and RXFP2 showed a dose-dependent increase in expression with estrogen. Progesterone treatment resulted in an increase while testosterone caused a dose-dependent decrease in the mRNA and protein expression of both relaxin receptor isoforms.

    DISCUSSION: Progesterone and high dose estrogen up-regulate while testosterone down-regulates RXFP1 and RXFP2 expression in the patellar tendon and lateral collateral ligament of rat's knee.

    CONCLUSION: Relaxin receptor isoforms up-regulation by progesterone and high dose estrogen could provide the basis for the reported increase in knee laxity while down-regulation of these receptor isoforms by testosterone could explain low incidence of non-contact knee injury in male.

    Matched MeSH terms: Receptors, G-Protein-Coupled/biosynthesis*; Receptors, G-Protein-Coupled/genetics
  12. Binding Hotspot and Activation Mechanism of Maltitol and Lactitol toward the Human Sweet Taste Receptor
    Mahalapbutr P, Lee VS, Rungrotmongkol T
    J Agric Food Chem, 2020 Jul 29;68(30):7974-7983.
    PMID: 32551626 DOI: 10.1021/acs.jafc.0c02580
    Human sweet taste receptor (hSTR) recognizes a wide array of sweeteners, resulting in sweet taste perception. Maltitol and lactitol have been extensively used in place of sucrose due to their capability to prevent dental caries. Herein, several molecular modeling approaches were applied to investigate the structural and energetic properties of these two polyols/hSTR complexes. Triplicate 500 ns molecular dynamics (MD) simulations and molecular mechanics/generalized Born surface area (MM/GBSA)-based free energy calculations revealed that the TAS1R2 monomer is the preferential binding site for maltitol and lactitol rather than the TAS1R3 region. Several polar residues (D142, S144, Y215, D278, E302, R383, and especially N143) were involved in polyols binding through electrostatic attractions and H-bond formations. The molecular complexation process not only induced the stable form of ligands but also stimulated the conformational adaptation of the TAS1R2 monomer to become a close-packed structure through an induced-fit mechanism. Notably, the binding affinity of the maltitol/TAS1R2 complex (ΔGbind of -17.93 ± 1.49 kcal/mol) was significantly higher than that of the lactitol/TAS1R2 system (-8.53 ± 1.78 kcal/mol), in line with the experimental relative sweetness. These findings provide an in-depth understanding of the differences in the sweetness response between maltitol and lactitol, which could be helpful to design novel polyol derivatives with higher sweet taste perception.
    Matched MeSH terms: Receptors, G-Protein-Coupled/genetics; Receptors, G-Protein-Coupled/metabolism*; Receptors, G-Protein-Coupled/chemistry
  13. Localization and characterization of val-opsin isoform-expressing cells in the brain of adult zebrafish
    Hang CY, Kitahashi T, Parhar IS
    J. Comp. Neurol., 2014 Dec 1;522(17):3847-60.
    PMID: 25043553 DOI: 10.1002/cne.23645
    In addition to vision, light information is used to regulate a range of animal physiology. Such nonimage-forming functions of light are mediated by nonvisual photoreceptors expressed in distinct neurons in the retina and the brain in most vertebrates. A nonvisual photoreceptor vertebrate ancient long opsin (VAL-opsin) possesses two functional isoforms in the zebrafish, encoded by valopa and valopb, which has received little attention. To delineate the neurochemical identities of valop cells and to test for colocalization of the valop isoforms, we used in situ hybridization to characterize the expression of the valop genes along with that of neurotransmitters and a neuropeptide known to be present at the sites of valop expression. Double labeling showed that the thalamic valop population coexpresses valopa and valopb. All the thalamic valop cells overlapped with a GABAergic cell mass that continues from the anterior nucleus to the intercalated thalamic nucleus. A novel valopa cell population found in the superior raphe was serotonergic in nature. A valopb cell population in the Edinger-Westphal nucleus was identified as containing thyrotropin-releasing hormone. Valopb cells localized in the hindbrain intermediate reticular formation were noncholinergic in nature (nonmotorneurons). Thus, the presence of valop cell populations in different brain regions with coexpression of neurotransmitters and neuropeptides and the colocalization of valop isoforms in the thalamic cell population indicate regulatory and functional complexity of VAL-opsin in the brain of the zebrafish.
    Matched MeSH terms: Receptors, G-Protein-Coupled/genetics; Receptors, G-Protein-Coupled/metabolism*
  14. Habenular Kiss1 neurons modulate the serotonergic system in the brain of zebrafish
    Ogawa S, Ng KW, Ramadasan PN, Nathan FM, Parhar IS
    Endocrinology, 2012 May;153(5):2398-407.
    PMID: 22454151 DOI: 10.1210/en.2012-1062
    The Kiss1/KISS1 gene has recently been implicated as a potent hypothalamic regulator of reproductive functions, in particular, the onset of puberty in mammals. In zebrafish (Danio rerio), there are two kiss1 homologues (kiss1 and kiss2) expressed in the brain: Kiss2-expressing neurons in the hypothalamic nuclei are considered potent regulators of reproduction, whereas the role of Kiss1-expressing neurons in the habenula remains unknown. We first analyzed the expression of kiss1 mRNA in a transgenic zebrafish, in which the habenula-interpeduncular nucleus (IPN) pathway is labelled with green fluorescent protein, and our application of a biocytin neural tracer into the habenula showed the presence of neuronal projections of Kiss1 neurons to the ventral IPN. Therefore, we speculated that kiss1 neurons might regulate the serotonergic system in the raphe. However, laser microdissection followed by real-time PCR revealed the expression of Kiss1 receptor (kissr1) mRNA in the habenula and the ventral IPN but not in the dorsal IPN or the serotonergic neurons in the raphe nuclei. Dual-fluorescent in situ hybridization revealed the coexpression of kiss1 and kissr1 mRNA in the habenula. Administration of Kiss1 significantly decreased the level of kiss1 mRNA (0.3- to 0.5-fold, P < 0.001), but the level of c-fos mRNA was increased (≈ 3-fold, P < 0.05) in the ventral habenula, suggesting that there is autocrine regulation of the kiss1 gene. Kiss1 administration significantly increased the c-fos mRNA levels in the raphe nuclei (2.5-fold, P < 0.001) and genes involved in the regulation of serotonin levels (pet1 and slc6a4a; 3.3- and 2.2-fold, P < 0.01). These findings suggest that the autocrine-regulated habenular Kiss1 neurons indirectly regulate the serotonergic system in the raphe nuclei through the IPN in the zebrafish.
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism*
  15. Fulltext Functional significance of GnRH and kisspeptin, and their cognate receptors in teleost reproduction
    Gopurappilly R, Ogawa S, Parhar IS
    Front Endocrinol (Lausanne), 2013;4:24.
    PMID: 23482509 DOI: 10.3389/fendo.2013.00024
    Guanine nucleotide binding protein (G-protein)-coupled receptors (GPCRs) are eukaryotic transmembrane proteins found in all living organisms. Their versatility and roles in several physiological processes make them the single largest family of drug targets. Comparative genomic studies using various model organisms have provided useful information about target receptors. The similarity of the genetic makeup of teleosts to that of humans and other vertebrates aligns with the study of GPCRs. Gonadotropin-releasing hormone (GnRH) represents a critical step in the reproductive process through its cognate GnRH receptors (GnRHRs). Kisspeptin (Kiss1) and its cognate GPCR, GPR54 (=kisspeptin receptor, Kiss-R), have recently been identified as a critical signaling system in the control of reproduction. The Kiss1/Kiss-R system regulates GnRH release, which is vital to pubertal development and vertebrate reproduction. This review highlights the physiological role of kisspeptin-Kiss-R signaling in the reproductive neuroendocrine axis in teleosts through the modulation of GnRH release. Moreover, we also review the recent developments in GnRHR and Kiss-R with respect to their structural variants, signaling mechanisms, ligand interactions, and functional significance. Finally, we discuss the recent progress in identifying many teleost GnRH-GnRHR and kisspeptin-Kiss-R systems and consider their physiological significance in the control of reproduction.
    Matched MeSH terms: Receptors, G-Protein-Coupled
  16. Fulltext Neuronal connectivity between habenular glutamate-kisspeptin1 co-expressing neurons and the raphe 5-HT system
    Nathan FM, Ogawa S, Parhar IS
    J Neurochem, 2015 Nov;135(4):814-29.
    PMID: 26250886 DOI: 10.1111/jnc.13273
    The habenula, located on the dorsal thalamic surface, is an emotional and reward processing center. As in the mammalian brain, the zebrafish habenula is divided into dorsal (dHb) and ventral (vHb) subdivisions that project to the interpeduncular nucleus and median raphe (MR) respectively. Previously, we have shown that kisspeptin 1 (Kiss1) expressing in the vHb, regulates the serotonin (5-HT) system in the MR. However, the connectivity between the Kiss1 neurons and the 5-HT system remains unknown. To resolve this issue, we generated a specific antibody against zebrafish Kiss1 receptor (Kiss-R1); using this primary antibody we found intense immunohistochemical labeling in the ventro-anterior corner of the MR (vaMR) but not in 5-HT neurons, suggesting the potential involvement of interneurons in 5-HT modulation by Kiss1. Double-fluorescence labeling showed that the majority of habenular Kiss1 neurons are glutamatergic. In the MR region, Kiss1 fibers were mainly seen in close association with glutamatergic neurons and only scarcely within GABAergic and 5-HT neurons. Our findings indicate that the habenular Kiss1 neurons potentially modulate the 5-HT system primarily through glutamatergic neurotransmission via as yet uncharacterized interneurons. The neuropeptide kisspeptin (Kiss1) play a key role in vertebrate reproduction. We have previously shown modulatory role of habenular Kiss1 in the raphe serotonin (5-HT) systems. This study proposed that the habenular Kiss1 neurons modulate the 5-HT system primarily through glutamatergic neurotransmission, which provides an important insight for understanding of the modulation of 5-HT system by the habenula-raphe pathway.
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism
  17. Fulltext Deep Brain Photoreceptor (val-opsin) Gene Knockout Using CRISPR/Cas Affects Chorion Formation and Embryonic Hatching in the Zebrafish
    Hang CY, Moriya S, Ogawa S, Parhar IS
    PLoS One, 2016;11(10):e0165535.
    PMID: 27792783 DOI: 10.1371/journal.pone.0165535
    Non-rod non-cone photopigments in the eyes and the brain can directly mediate non-visual functions of light in non-mammals. This was supported by our recent findings on vertebrate ancient long (VAL)-opsin photopigments encoded by the val-opsinA (valopa) and val-opsinB (valopb) genes in zebrafish. However, the physiological functions of valop isoforms remain unknown. Here, we generated valop-mutant zebrafish using CRISPR/Cas genome editing, and examined the phenotypes of loss-of-function mutants. F0 mosaic mutations and germline transmission were confirmed via targeted insertions and/or deletions in the valopa or valopb gene in F1 mutants. Based on in silico analysis, frameshift mutations converted VAL-opsin proteins to non-functional truncated forms with pre-mature stop codons. Most F1 eggs or embryos from F0 female valopa/b mutants showed either no or only partial chorion elevation, and the eggs or embryos died within 26 hour-post-fertilization. However, most F1 embryos from F0 male valopa mutant developed but hatched late compared to wild-type embryos, which hatched at 4 day-post-fertilization. Late-hatched F1 offspring included wild-type and mutants, indicating the parental effects of valop knockout. This study shows valop gene knockout affects chorion formation and embryonic hatching in the zebrafish.
    Matched MeSH terms: Receptors, G-Protein-Coupled/deficiency; Receptors, G-Protein-Coupled/genetics*; Receptors, G-Protein-Coupled/chemistry
  18. Anatomy of the kisspeptin systems in teleosts
    Ogawa S, Parhar IS
    Gen Comp Endocrinol, 2013 Jan 15;181:169-74.
    PMID: 22967958 DOI: 10.1016/j.ygcen.2012.08.023
    Kisspeptin and its cognate receptor, GPR54 (kisspeptin receptor, Kiss-R) have recently been recognized potent regulators of reproduction in vertebrates. In non-mammalian vertebrates, kisspeptin-Kiss-R homologous and paralogous genes have been identified with their conserved functions in reproduction. Teleosts possess two paralogous genes encoding kisspeptin (kiss1 and kiss2) and Kiss-R (kissr1 and kissr2). Identification of the location and the distribution of the kisspeptin-Kiss-R systems as well as their connectivity with other neural system in the brain is important to elucidate the role of kisspeptin in neuroendocrine functions. This review focuses on the comparative aspects of neuroanatomical distribution of two kisspeptin-Kiss-R systems in the brain of teleosts and their potential roles in reproductive and non-reproductive functions. Finally, based on the association of kisspeptin types with tachykinin peptides, their potential neuromodulatory roles in the brain of teleost will be discussed. The existence of two kisspeptin systems suggests their independent functions in the brain of teleosts. Understanding of teleosts Kiss1 and Kiss2 systems will provide insight into the physiological and evolutional significance of multiple kisspeptin systems in the vertebrate brain.
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism
  19. Fulltext JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma
    Nairismägi ML, Tan J, Lim JQ, Nagarajan S, Ng CC, Rajasegaran V, et al.
    Leukemia, 2016 06;30(6):1311-9.
    PMID: 26854024 DOI: 10.1038/leu.2016.13
    Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism*
  20. Fulltext Platelet-activating factor (PAF) antagonistic activity of a new biflavonoid from Garcinia nervosa var. pubescens King
    Jalil J, Jantan I, Ghani AA, Murad S
    Molecules, 2012 Sep 10;17(9):10893-901.
    PMID: 22964504 DOI: 10.3390/molecules170910893
    The methanol extract of the leaves of Garcinia nervosa var. pubescens King, which showed strong inhibitory effects on platelet-activating factor (PAF) receptor binding, was subjected to bioassay-guided isolation to obtain a new biflavonoid, II-3,I-5, II-5,II-7,I-4',II-4'-hexahydroxy-(I-3,II-8)-flavonylflavanonol together with two known flavonoids, 6-methyl-4'-methoxyflavone and acacetin. The structures of the compounds were elucidated by spectroscopic methods. The compounds were evaluated for their ability to inhibit PAF receptor binding to rabbit platelets using ³H-PAF as a ligand. The biflavonoid and acacetin showed strong inhibition with IC₅₀ values of 28.0 and 20.4 µM, respectively. The results suggest that these compounds could be responsible for the strong PAF antagonistic activity of the plant.
    Matched MeSH terms: Receptors, G-Protein-Coupled/antagonists & inhibitors*; Receptors, G-Protein-Coupled/metabolism
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