Displaying publications 1 - 20 of 55 in total

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  1. Evaluating the performance of MM/PBSA for binding affinity prediction using class A GPCR crystal structures
    Yau MQ, Emtage AL, Chan NJY, Doughty SW, Loo JSE
    J Comput Aided Mol Des, 2019 05;33(5):487-496.
    PMID: 30989574 DOI: 10.1007/s10822-019-00201-3
    The recent expansion of GPCR crystal structures provides the opportunity to assess the performance of structure-based drug design methods for the GPCR superfamily. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA)-based methods are commonly used for binding affinity prediction, as they provide an intermediate compromise of speed and accuracy between the empirical scoring functions used in docking and more robust free energy perturbation methods. In this study, we systematically assessed the performance of MM/PBSA in predicting experimental binding free energies using twenty Class A GPCR crystal structures and 934 known ligands. Correlations between predicted and experimental binding free energies varied significantly between individual targets, ranging from r = - 0.334 in the inactive-state CB1 cannabinoid receptor to r = 0.781 in the active-state CB1 cannabinoid receptor, while average correlation across all twenty targets was relatively poor (r = 0.183). MM/PBSA provided better predictions of binding free energies compared to docking scores in eight out of the twenty GPCR targets while performing worse for four targets. MM/PBSA binding affinity predictions calculated using a single, energy minimized structure provided comparable predictions to sampling from molecular dynamics simulations and may be more efficient when computational cost becomes restrictive. Additionally, we observed that restricting MM/PBSA calculations to ligands with a high degree of structural similarity to the crystal structure ligands improved performance in several cases. In conclusion, while MM/PBSA remains a valuable tool for GPCR structure-based drug design, its performance in predicting the binding free energies of GPCR ligands remains highly system-specific as demonstrated in a subset of twenty Class A GPCRs, and validation of MM/PBSA-based methods for each individual case is recommended before prospective use.
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism; Receptors, G-Protein-Coupled/chemistry*
  2. Molecular signaling of G-protein-coupled receptor in chronic heart failure and associated complications
    Altamish M, Samuel VP, Dahiya R, Singh Y, Deb PK, Bakshi HA, et al.
    Drug Dev Res, 2020 02;81(1):23-31.
    PMID: 31785110 DOI: 10.1002/ddr.21627
    The well-known condition of heart failure is a clinical syndrome that results when the myocardium's ability to pump enough blood to meet the body's metabolic needs is impaired. Most of the cardiac activity is maintained by adrenoceptors, are categorized into two main α and β and three distinct subtypes of β receptor: β1-, β2-, and β3-adrenoceptors. The β adrenoreceptor is the main regulatory macro proteins, predominantly available on heart and responsible for down regulatory cardiac signaling. Moreover, the pathological involvement of Angiotensin-converting enzyme 1 (ACE1)/angiotensin II (Ang II)/angiotensin II type 1 (AT1) axis and beneficial ACE2/Ang (1-7)/Mas receptor axis also shows protective role via Gi βγ, during heart failure these receptors get desensitized or internalized due to increase in the activity of G-protein-coupled receptor kinase 2 (GRK2) and GRK5, responsible for phosphorylation of G-protein-mediated down regulatory signaling. Here, we investigate the various clinical and preclinical data that exhibit the molecular mechanism of upset level of GRK change the cardiac activity during failing heart.
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism*
  3. 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
  4. 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
  5. Fulltext 20-Hydroxyeicosatetraenoic acid (20-HETE): Bioactions, receptors, vascular function, cardiometabolic disease and beyond
    Pascale JV, Wolf A, Kadish Y, Diegisser D, Kulaprathazhe MM, Yemane D, et al.
    Adv Pharmacol, 2023;97:229-255.
    PMID: 37236760 DOI: 10.1016/bs.apha.2023.01.002
    Vascular function is dynamically regulated and dependent on a bevy of cell types and factors that work in concert across the vasculature. The vasoactive eicosanoid, 20-Hydroxyeicosatetraenoic acid (20-HETE) is a key player in this system influencing the sensitivity of the vasculature to constrictor stimuli, regulating endothelial function, and influencing the renin angiotensin system (RAS), as well as being a driver of vascular remodeling independent of blood pressure elevations. Several of these bioactions are accomplished through the ligand-receptor pairing between 20-HETE and its high-affinity receptor, GPR75. This 20-HETE axis is at the root of various vascular pathologies and processes including ischemia induced angiogenesis, arteriogenesis, septic shock, hypertension, atherosclerosis, myocardial infarction and cardiometabolic diseases including diabetes and insulin resistance. Pharmacologically, several preclinical tools have been developed to disrupt the 20-HETE axis including 20-HETE synthesis inhibitors (DDMS and HET0016), synthetic 20-HETE agonist analogues (20-5,14-HEDE and 20-5,14-HEDGE) and 20-HETE receptor blockers (AAA and 20-SOLA). Systemic or cell-specific therapeutic targeting of the 20-HETE-GPR75 axis continues to be an invaluable approach as studies examine the molecular underpinnings activated by 20-HETE under various physiological settings. In particular, the development and characterization of 20-HETE receptor blockers look to be a promising new class of compounds that can provide a considerable benefit to patients suffering from these cardiovascular pathologies.
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism
  6. Benchmarking the performance of MM/PBSA in virtual screening enrichment using the GPCR-Bench dataset
    Yau MQ, Emtage AL, Loo JSE
    J Comput Aided Mol Des, 2020 Nov;34(11):1133-1145.
    PMID: 32851579 DOI: 10.1007/s10822-020-00339-5
    Recent breakthroughs in G protein-coupled receptor (GPCR) crystallography and the subsequent increase in number of solved GPCR structures has allowed for the unprecedented opportunity to utilize their experimental structures for structure-based drug discovery applications. As virtual screening represents one of the primary computational methods used for the discovery of novel leads, the GPCR-Bench dataset was created to facilitate comparison among various virtual screening protocols. In this study, we have benchmarked the performance of Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) in improving virtual screening enrichment in comparison to docking with Glide, using the entire GPCR-Bench dataset of 24 GPCR targets and 254,646 actives and decoys. Reranking the top 10% of the docked dataset using MM/PBSA resulted in improvements for six targets at EF1% and nine targets at EF5%, with the gains in enrichment being more pronounced at the EF1% level. We additionally assessed the utility of rescoring the top ten poses from docking and the ability of short MD simulations to refine the binding poses prior to MM/PBSA calculations. There was no clear trend of the benefit observed in both cases, suggesting that utilizing a single energy minimized structure for MM/PBSA calculations may be the most computationally efficient approach in virtual screening. Overall, the performance of MM/PBSA rescoring in improving virtual screening enrichment obtained from docking of the GPCR-Bench dataset was found to be relatively modest and target-specific, highlighting the need for validation of MM/PBSA-based protocols prior to prospective use.
    Matched MeSH terms: Receptors, G-Protein-Coupled
  7. 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
  8. Toward activated homology models of the human M1 muscarinic acetylcholine receptor
    Chin SP, Buckle MJ, Chalmers DK, Yuriev E, Doughty SW
    J Mol Graph Model, 2014 Apr;49:91-8.
    PMID: 24631873 DOI: 10.1016/j.jmgm.2014.02.002
    Structure-based virtual screening offers a good opportunity for the discovery of selective M1 muscarinic acetylcholine receptor (mAChR) agonists for the treatment of Alzheimer's disease. However, no 3-D structure of an M1 mAChR is yet available and the homology models that have been previously reported are only able to identify antagonists in virtual screening experiments. In this study, we generated a homology model of the human M1 mAChR, based on the crystal structure of an M3 mAChR as the template. This initial model was modified, using the agonist-bound crystal structure of a β2-adrenergic receptor as a guide, to give two possible activated structures. The T192 side chain was adjusted in both structures and one of the structures also had the whole of transmembrane (TM) 5 rotated and tilted toward the inner channel of the transmembrane region. The binding sites of all three structures were then refined by induced-fit docking (IFD) with acetylcholine. Virtual screening experiments showed that all three refined models could efficiently differentiate agonists from decoy molecules, with the TM5-modified models also giving good agonist/antagonist selectivity. The whole range of agonists and antagonists was observed to bind within the orthosteric site of the structure obtained by IFD refinement alone, implying that it has inactive state character. In contrast, the two TM5-modified structures were unable to accommodate the antagonists, supporting the proposition that they possess activated state character.
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism; Receptors, G-Protein-Coupled/chemistry
  9. G protein-coupled estrogen receptor-1: homology modeling approaches and application in screening new GPER-1 modulators
    Khan SU, Ahemad N, Chuah LH, Naidu R, Htar TT
    J Biomol Struct Dyn, 2020 Nov 08.
    PMID: 33164654 DOI: 10.1080/07391102.2020.1844059
    G protein-coupled receptors (GPCRs) belong to the largest family of protein targets comprising over 800 members in which at least 500 members are the therapeutic targets. Among the GPCRs, G protein-coupled estrogen receptor-1 (GPER-1) has shown to have the ability in estrogen signaling. As GPER-1 plays a critical role in several physiological responses, GPER-1 has been considered as a potential therapeutic target to treat estrogen-based cancers and other non-communicable diseases. However, the progress in the understanding of GPER-1 structure and function is relatively slow due to the availability of a only a few selective GPER-1 modulators. As with many GPCRs, the X-ray crystal structure of GPER-1 is yet to be resolved and thus has led the researchers to search for new GPER-1 modulators using homology models of GPER-1. In this review, we aim to summarize various approaches used in the generation of GPER-1 homology model and their applications that have resulted in new GPER-1 ligands.
    Matched MeSH terms: Receptors, G-Protein-Coupled
  10. 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
  11. Fulltext Distribution of 5-HT3, 5-HT4, and 5-HT7 Receptors Along the Human Colon
    Yaakob NS, Chinkwo KA, Chetty N, Coupar IM, Irving HR
    J Neurogastroenterol Motil, 2015 Jul 30;21(3):361-9.
    PMID: 26130632 DOI: 10.5056/jnm14157
    Several disorders of the gastrointestinal tract are associated with abnormal serotonin (5-HT) signaling or metabolism where the 5-HT3 and 5-HT4 receptors are clinically relevant. The aim was to examine the distribution of 5-HT3, 5-HT4, and 5-HT7 receptors in the normal human colon and how this is associated with receptor interacting chaperone 3, G protein coupled receptor kin-ases, and protein LIN-7 homologs to extend previous observations limited to the sigmoid colon or the upper intestine.
    Matched MeSH terms: Receptors, G-Protein-Coupled
  12. 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*
  13. Fulltext COVID-19 transmission through host cell directed network of GPCR
    Singh Y, Gupta G, Satija S, Pabreja K, Chellappan DK, Dua K
    Drug Dev Res, 2020 09;81(6):647-649.
    PMID: 32329083 DOI: 10.1002/ddr.21674
    Matched MeSH terms: Receptors, G-Protein-Coupled/metabolism*
  14. Fulltext The kiss/kissr systems are dispensable for zebrafish reproduction: evidence from gene knockout studies
    Tang H, Liu Y, Luo D, Ogawa S, Yin Y, Li S, et al.
    Endocrinology, 2015 Feb;156(2):589-99.
    PMID: 25406015 DOI: 10.1210/en.2014-1204
    The kiss1/gpr54 signaling system is considered to be a critical regulator of reproduction in most vertebrates. However, this presumption has not been tested vigorously in nonmammalian vertebrates. Distinct from mammals, multiple kiss1/gpr54 paralogous genes (kiss/kissr) have been identified in nonmammalian vertebrates, raising the possibility of functional redundancy among these genes. In this study, we have systematically generated the zebrafish kiss1(-/-), kiss2(-/-), and kiss1(-/-);kiss2(-/-) mutant lines as well as the kissr1(-/-), kissr2(-/-), and kissr1(-/-);kissr2(-/-) mutant lines using transcription activator-like effector nucleases. We have demonstrated that spermatogenesis and folliculogenesis as well as reproductive capability are not impaired in all of these 6 mutant lines. Collectively, our results indicate that kiss/kissr signaling is not absolutely required for zebrafish reproduction, suggesting that the kiss/kissr systems play nonessential roles for reproduction in certain nonmammalian vertebrates. These findings also demonstrated that fish and mammals have evolved different strategies for neuroendocrine control of reproduction.
    Matched MeSH terms: Receptors, G-Protein-Coupled/genetics; Receptors, G-Protein-Coupled/metabolism*
  15. 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*
  16. Platelet-activating factor (PAF) receptor binding activity of the roots of Enicosanthellum pulchrum
    Nordin N, Jalil J, Jantan I, Murad S
    Pharm Biol, 2012 Mar;50(3):284-90.
    PMID: 22103812 DOI: 10.3109/13880209.2011.602416
    Enicosanthellum pulchrum (King) Heusden (Annonaceae) is a coniferous tree that is confined to mountain forests. The chemical constituents of this species have been studied previously; however, its biological activity has never been investigated before and is reported here for the first time.
    Matched MeSH terms: Receptors, G-Protein-Coupled/antagonists & inhibitors*; Receptors, G-Protein-Coupled/metabolism
  17. GPCR drug discovery: novel ligands for CNS receptors
    Lim WK
    Recent Pat CNS Drug Discov, 2007 Jun;2(2):107-12.
    PMID: 18221221
    G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in humans. They convey extracellular signals into the cell interior by activating intracellular processes such as heterotrimeric G protein-dependent signaling pathways. They are widely distributed in the nervous system, and mediate key physiological processes including cognition, mood, appetite, pain and synaptic transmission. With at least 30% of marketed drugs being GPCR modulators, they are a major therapeutic target in the pharmaceutical industry's drug discovery programs. This review will survey recently patented ligands for GPCRs implicated in CNS disorders, in particular the metabotropic glutamate, adenosine and cannabinoid receptors. Metabotropic glutamate receptors regulate signaling by glutamate, the major excitatory brain neurotransmitter, while adenosine is a ubiquitous neuromodulater mediating diverse physiological effects. Recent patents for ligands of these receptors include mGluR5 antagonists and adenosine A(1) receptor agonists. Cannabinoid receptors remain one of the most important GPCR drug discovery target due to the intense interest in CB(1) receptor antagonists for treating obesity and metabolic syndrome. Such small molecule ligands are the outcome of the continuing focus of many pharmaceutical companies to identify novel GPCR agonist, antagonist or allosteric modulators useful for CNS disorders, for which more effective drugs are eagerly awaited.
    Matched MeSH terms: Receptors, G-Protein-Coupled/drug effects*; Receptors, G-Protein-Coupled/metabolism
  18. 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
  19. 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
  20. Luteolin, a Potent Human Monoamine Oxidase-A Inhibitor and Dopamine D4 and Vasopressin V1A Receptor Antagonist
    Park SE, Paudel P, Wagle A, Seong SH, Kim HR, Fauzi FM, et al.
    J Agric Food Chem, 2020 Sep 30;68(39):10719-10729.
    PMID: 32869630 DOI: 10.1021/acs.jafc.0c04502
    Luteolin, a flavonoid widely distributed in the plant kingdom, contains two benzene rings and hydroxyl groups, and this structural specificity contributes to its diverse biological activities. However, no previous studies have simultaneously investigated the therapeutic potency of luteolin isolated from a plant as an antipsychotic and antidepressant. Here, luteolin exhibited selective inhibition of hMAO-A (IC50 = 8.57 ± 0.47 μM) over hMAO-B (IC50 > 100 μM). In silico proteochemometric modeling predicted promising targets of luteolin, and verification via cell-based G protein-coupled receptor functional assays showed that luteolin is a selective antagonist of the vasopressin receptor V1AR (IC50 = 19.49 ± 6.32 μM) and the dopamine D4 receptor (IC50 = 39.59 ± 1.46 μM). Molecular docking showed the tight binding of luteolin with a low binding score and the high stability of the luteolin-receptor complex, corroborating its functional effect. Thus, hMAO-A, hD4R, and hV1AR are prime targets of luteolin and potential alternatives for the management of neurodegenerative diseases.
    Matched MeSH terms: Receptors, G-Protein-Coupled
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