Skip to main content
SpringerLink
Log in

Therapeutically Targeting TGR5 and P2Y Receptors

  • Chapter
  • First Online:
Metabotropic GPCRs: TGR5 and P2Y Receptors in Health and Diseases

  • 336 Accesses

Abstract

A few cell surface receptors of bile acids have been discovered so far. TGR5 is a membrane-bound G-protein-coupled receptor for bile acids that are found in several types of tissues types, including liver. TGR5 is involved in a number of important biological processes, such as controlling the energy balance, insulin and glucose homeostasis, inflammation, bile formation and secretion, intestinal motility and secretion, and bile acid -evoked itch and analgesia. The neurons of the enteric and central nervous system also express TGR5 and it is involved in the intestinal motility and detection of endogenous neurosteroids in response to bile acids. The role of TGR5 against metabolic, inflammatory and digestive diseases is becoming prominent and the agonists of TGR5 may promote energy expenditure and insulin release, inflammation, and promote colon transit. Many of the recent reviews have described the conditions in which TGR5 could be a promising new target for pharmaceutical agents. Hence, it becomes important to delineate how these agonists regulate TGR5. The expression and/or activities of P2Ys are highly altered in cells and tissues during the disease progression and more than one P2Ys are involved in many cases. The growing bodies of evidences from experimental and clinical studies emphasize the potential therapeutic value of members of P2Y. As they are considered to be a new therapeutic strategy, several pharmacological agents targeting P2Y receptors are presently available in the market and many of them are under clinical trials. This present chapter summarize the present knowledge on therapeutic significance of TGR5 and P2Y receptors and to reveal the plausible therapeutic use of agents targeting these receptors in the treatment of human diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Albalawi, F., Lu, W., Beckel, J., Lim, J., McCaughey, S., & Mitchell, C. (2017). The P2X7 receptor primes IL-1β and the NLRP3 inflammasome in astrocytes exposed to mechanical strain. Frontiers in Cellular Neuroscience, 11, 227.

    Article  PubMed  PubMed Central  Google Scholar 

  • Alemi, F., Poole, D., Chiu, J., Schoonjans, K., Cattaruzza, F., Grider, J., Bunnett, N., & Corvera, C. (2013). The receptor TGR5 mediates the Prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology, 144, 145–154.

    Article  CAS  PubMed  Google Scholar 

  • Bala, V., Rajagopal, S., Kumar, D. P., Nalli, A. D., Mahavadi, S., Sanyal, A. J., Grider, J. R., & Murthy, K. S. (2014). Release of GLP-1 and PYY in response to the activation of G-protein coupled bile acid receptor TGR5 is mediated by Epac/PLC e pathway and modulated by endogenous H2S. Frontiers in Physiology, 5, 1–11.

    Article  Google Scholar 

  • Bijvelds, M., Jorna, H., Verkade, H., Bot, A., Hofmann, F., Agellon, L., Sinaasappel, M., & de Jonge, H. (2005). Activation of CFTR by ASBT-mediated bile salt absorption. American Journal of Physiology; Gastrointestinal and Liver physiology, 289, G870–G879.

    Article  CAS  PubMed  Google Scholar 

  • Bunnett, N., & Cottrell, G. (2010). Trafficking and signaling of G protein-coupled receptors in the nervous system: Implications for disease and therapy. CNS Neurological Disorders and Drug Targets, 9, 539–556.

    Article  CAS  Google Scholar 

  • Burch, L., & Picher, M. (2006). E-NTPDases in human airways: Regulation and relevance for chronic lung diseases. Purinergic Signalling, 2, 399–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burnstock, G. (2016). Purinergic signalling in the gut. Advanced Experimental and Medical Biology, 891, 91–112.

    Article  CAS  Google Scholar 

  • Burnstock, G., & Loesch, A. (2017). Sympathetic innervation of the kidney in health and disease: Emphasis on the role of purinergic cotransmission. Auton Neuroscience, 204, 4–16.

    Article  CAS  Google Scholar 

  • Bourdon, D. M., Mahanty, S. K., Jacobson, K. A., Boyer, J. L., & Harden, T. K. (2006). (N)-methanocarba-2MeSADP (MRS2365) is a subtype-specific agonist that induces rapid desensitization of the P2Y1 receptor of human platelets. Journal of Thrombosis and Haemostasis, 4, 861–868.

    Article  CAS  PubMed  Google Scholar 

  • Cattaneo, G., Podda, G., & Cattaneo, M. (2011). Recent advances on the studies of the platelet’s inhibition and aggregation. State of the art of new P2Y12 antagonists. Recent Progressive Medicine, 102, 150–155.

    Google Scholar 

  • Cattaneo, F., Guerra, G., Parisi, M., De Marinis, M., Tafuri, D., Cinelli, M., & Ammendola, R. (2014). Cell-surface receptors transactivation mediated by g protein-coupled receptors. International Journal of Molecular Sciences, 15, 19700–19728.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen, X., Lou, G., Meng, Z., & Huang, W. (2011). TGR5: A novel target for weight maintenance and glucose metabolism. Experimental Diabetes Research, 2011, 1–5.

    Google Scholar 

  • Chhatriwala, M., Gnana Ravi, G., Patel, R., Boyer, J., Jacobson, K., & Kendall Harden, T. (2004). Induction of novel agonist selectivity for the ADP-activated P2Y1 receptor versus the ADP-activated P2Y12 and P2Y13 receptors by conformational constraint of an ADP analog. Journal of Pharmacology and Experimental Therapeutics, 311, 1038–1043.

    Article  CAS  Google Scholar 

  • Damman, P., Woudstra, P., Kuijt, W., de Winter, R., & James, S. (2012). P2Y12 platelet inhibition in clinical practice. Journal of Thrombosis and Thrombolysis, 33, 143–153.

    Article  CAS  PubMed  Google Scholar 

  • Dawson, P. (2011). Role of the intestinal bile acid transporters in bile acid and drug disposition. Handbook of Experimental Pharmacology, 201, 169–203.

    Article  CAS  Google Scholar 

  • Delesque-Touchard, N., Pendaries, C., Volle-Challier, C., Millet, L., Salel, V., Hervé, C., Pflieger, A., Berthou-Soulie, L., Prades, C., Sorg, T., Jean-Marc, H., Savi, P., & Bono, F. (2014). Regulator of G-protein signaling 18 controls both platelet generation and function. PLOS One, 9(11), e113215.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • do Carmo, J., da Silva, A., Ebaady, S., Sessums, P., Abraham, R., Elmquist, J., Lowell, B., & Hall, J. (2014). Shp2 signaling in POMC neurons is important for leptin’s actions on blood pressure, energy balance, and glucose regulation. American Journal of Physiology: Regulatory and Integrative Compartive Physiology, 307, R1438–R1447.

    Google Scholar 

  • Dreisig, K., & Rahbek, B. (2016). A critical look at the function of the P2Y11 receptor. Purinergic Signalling, 12, 427–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duboc, H., Taché, Y., & Hofmann, A. (2014). The bile acid TGR5 membrane receptor: From basic research to clinical application. Digestive Liver Diseases, 46, 302–312.

    Article  CAS  Google Scholar 

  • Dufer, M., Hörth, K., Krippeit-Drews, P., & Drews, G. (2012). The significance of the nuclear farnesoid X receptor (FXR) in beta cell function. Islets, 4, 333–338.

    Article  PubMed  PubMed Central  Google Scholar 

  • Evans, K., Budzik, B., Ross, S., Wisnoski, D., Jin, J., Rivero, R., Vimal, M., Szewczyk, G., Jayawickreme, C., Monco, D., Rimele, T., Armour, S., Weaver, S., Griffin, R., Tadepalli, S., Jeune, M., Shearer, T., Chen, Z., Chen, L., Anderson, D., Becherer, J., De Los Frailes, M., & Javier Colilla, F. (2009). Discovery of 3-Aryl-4-isoxazolecarboxamides as TGR5 receptor agonists. Journal of Medicinal Chemistry, 52, 7962–7965.

    Article  CAS  PubMed  Google Scholar 

  • Faria, D., Schreiber, R., & Karl, K. (2009). CFTR is activated through stimulation of purinergic P2Y2 receptors. Pflügers Archiv – European Journal of Physiology, 457, 1373–1380.

    Article  CAS  PubMed  Google Scholar 

  • Farret, A., Filhol, R., Linck, N., Manteghetti, M., Vignon, J., Gross, R., & Petit, P. (2006). P2Y receptor mediated modulation of insulin release by a novel generation of 2-substituted-5′-O-(1-boranotriphosphate)-adenosine analogues. Pharmaceutical Research, 23, 2665–2671.

    Article  CAS  PubMed  Google Scholar 

  • Gertzen, C., Spomer, L., Smits, S., Häussinger, D., Keitel, V., & Gohlke, H. (2015). Mutational mapping of the transmembrane binding site of the G-protein coupled receptor TGR5 and binding mode prediction of TGR5 agonists. European Journal of Medicinal Chemistry, 104, 57–72.

    Article  CAS  PubMed  Google Scholar 

  • Gremmel, T., Yanachkov, I., Yanachkova, M., Wright, G., Wider, J., Vishnu, V., Michelson, A., Frelinger, A. I., & Przyklenk, K. (2016). Synergistic inhibition of both P2Y1 and P2Y12 adenosine diphosphate receptors as novel approach to rapidly attenuate platelet-mediated thrombosis. Arteriosclerosis Thrombosis and Vascular Biology, 36, 501–509.

    Article  CAS  Google Scholar 

  • Guo, C., Chen, W., & Wang, Y. (2016). TGR5, not only a metabolic regulator. Frontiers in Physiology, 7, 646.

    PubMed  PubMed Central  Google Scholar 

  • Hana, A., Deborah, M., & Ali, S. (2014). Secondary bile acids: An underrecognized cause of colon cancer. World Journal of Surgery Oncology, 12, 164.

    Article  Google Scholar 

  • Handelsman, Y. (2011). Role of bile acid sequestrants in the treatment of type 2 diabetes. Diabetes Care, 34, S244–S250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hauser, A., Attwood, M., Rask-Andersen, M., Schiöth, H., & Gloriam, D. (2017). Trends in GPCR drug discovery: New agents, targets and indications. Nature Reviews Drug Discovery, 16, 829–842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hauser, A., Chavali, S., Ikuo, M., Leonie, J., Martemyanov, K., Gloriam, D., & MadanBabu, M. (2018). Pharmacogenomics of GPCR drug targets. Cell, 172, 41–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hill, M. (1990). Bile flow and colon cancer. Mutation Research, 238, 313–320.

    Article  CAS  PubMed  Google Scholar 

  • Hochhauser, E., Cohen, R., Waldman, M., Maksin, A., Isak, A., Aravot, D., Jayasekara, P., Müller, C., Jacobson, K., & Shainberg, A. (2013). P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo. Purinergic Signalling, 9, 633–642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hodge, R., & Nunez, D. (2016). Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype? Diabetes Obese and metabolism, 18, 439–443.

    Article  CAS  Google Scholar 

  • Ichikawa, R., Takayama, T., Yoneno, K., Kamada, N., Kitazume, M., Higuchi, H., Matsuoka, K., Watanabe, M., Itoh, H., Kanai, T., Hisamatsu, T., & Hibi, T. (2012). Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. Immunology, 136, 153–162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jenkins, G., Cronin, J., Alhamdani, A., Rawat, N., D’souza, F., Thomas, T., Eltahir, Z., Griffiths, A., & Baxter, J. (2008). The bile acid deoxycholic acid has a non-linear dose response for DNA damage and possibly NF-kappaB activation in oesophageal cells, with a mechanism of action involving ROS. Mutagenesis, 23, 399–405.

    Article  CAS  PubMed  Google Scholar 

  • Jiang, J., & Dingledine, R. (2013). Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. Trends in Pharmacological Sciences, 34, 413–423.

    Article  CAS  PubMed  Google Scholar 

  • Kaia, M., Tarjei, H., Ellen, K., CR, K., & Lea, T. (2014). Activation of the bile acid receptor TGR5 enhances LPS-induced inflammatory responses in a human monocytic cell line. Journal of Receptor and Signal Transduction, 35, 402–409.

    Google Scholar 

  • Kauffenstein, G., Tamareille, S., Prunier, F., Roy, C., Ayer, A., Toutain, B., Billaud, M., Isakson, B., Grimaud, L., Loufrani, L., Rousseau, P., Abraham, P., Procaccio, V., Monyer, H., de Wit, C., Boeynaems, J., Robaye, B., Kwak, B., & Henrion, D. (2016). Central role of P2Y6 UDP receptor in arteriolar myogenic tone. Arteriosclerosis Thrombsis and Vascular Biology, 36, 1598–1606.

    Article  CAS  Google Scholar 

  • Keitel, V., & Häussinger, D. (2011). TGR5 in the biliary tree. Digestive Diseases, 29, 45–47.

    Article  PubMed  CAS  Google Scholar 

  • Keitel, V., Reinehr, R., Gatsios, P., Rupprecht, C., Görg, B., Selbach, O., Häussinger, D., & Kubitz, R. H. (2007). The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology, 45, 695–704.

    Article  CAS  PubMed  Google Scholar 

  • Keitel, V., Spomer, L., Marin, J., Williams, R., Geenes, V., Kubitz, R., Haussinger, D., & Macias, R. (2013). Effect of maternal cholestasis on TGR5 expression in human and rat placenta at term. Placenta, 34, 810–816.

    Article  CAS  PubMed  Google Scholar 

  • Khalid, S., Akram, U., Hassan, T., Nasim, A., & Jameel, A. (2017). Fully automated robust system to detect retinal edema, central serous Chorioretinopathy, and age related macular degeneration from optical coherence tomography images. Biomedical Research International, 2017, 7148245.

    Article  Google Scholar 

  • Kida, T., Tsubosaka, Y., Hori, M., Ozaki, H., & Murata, T. (2013). Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells. Arteriosclerosis Thrombosis and Vascular Biology, 33, 1663–1669.

    Article  CAS  Google Scholar 

  • Kim, L., Mertens, A., Maarten, R., & Hannah, M. (2017). Bile acid signaling pathways from the enterohepatic circulation to the central nervous system. Frontiers in Neuroscience, 11, 1–9.

    Google Scholar 

  • Kumar, D. P., Senthilkumar, R., Sunila, M., Faridoddin, M., Grider, J., Murthy, K., & Sanyal, A. (2012). Activation of transmembrane bile acid receptor TGR5 stimulates both insulin gene transcription and insulin release in pancreatic b cells. Biochemical and Biophysical Research Communication, 427, 600–605.

    Article  CAS  Google Scholar 

  • Kwang-Hoon, S., Li, T., Owsley, E., Strom, S., & Chiang, J. (2009). Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7α-hydroxylase gene expression. Hepatology, 49, 297–305.

    Article  CAS  Google Scholar 

  • Lane, J., May, L., Parton, R., Sexton, P., & Christopoulos, A. (2017). A kinetic view of GPCR allostery and biased agonism. Nature: Chemical Biology, 13, 929–937.

    CAS  Google Scholar 

  • Lau, O., Samarawickrama, C., & Skalicky, S. (2014). P2Y2 receptor agonists for the treatment of dry eye disease: A review. Clinical Ophthalmology, 8, 327–334.

    PubMed  PubMed Central  Google Scholar 

  • Lavoie, B., Balemba, O., Godfrey, C., Watson, C., Vassileva, G., Corvera, C., Nelson, M., & Mawe, G. (2010). Hydrophobic bile salts inhibit gallbladder smooth muscle function via stimulation of GPBAR1 receptors and activation of KATP channels. Journal of Physiology, 588, 3295–3305.

    Article  CAS  Google Scholar 

  • Li, T., Holmstrom, S. R., Kir, S., Umetani, M., Schmidt, D., Kliewer, S., & Mangelsdorf, D. (2011). The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Molecular Endocrinology, 25, 1066–1071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lieu, T., Jayaweera, G., Zhao, P., Poole, D., Jensen, D., Grace, M., McIntyre, P., Bron, R., Wilson, Y., Krappitz, M., Haerteis, S., Korbmacher, C., Steinhoff, M., Nassini, R., Materazzi, S., Geppetti, P., Corvera, C., & Bunnett, N. (2014). The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology, 147, 1417–1428.

    Article  CAS  PubMed  Google Scholar 

  • Masyuk, A., Huang, B., Radtke, B., Gajdos, G., Splinter, P., Masyuk, T., Gradilone, S., & LaRusso, N. (2013). Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. American Journal of Physiology: Gastrointestinal and Liver Physiology, 304, G1013–G1024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michal, H., Talia, W., & Moshe, L. (2018). Bile acid receptors and the kidney. Current Opinion in Nephrology and Hypertension, 27, 56–62.

    Article  Google Scholar 

  • Min-Chan, C., Yi-Ling, C., Tzu-Wen, W., Hui-Ping, H., & Ming-Derg, L. (2016). Membrane bile acid receptor TGR5 predicts good prognosis in ampullary adenocarcinoma patients with hyperbilirubinemia. Oncology Report, 36, 1997–2008.

    Article  CAS  Google Scholar 

  • Muller, D., Zimmering, M., & Roehr, C. C. (2004). Should nifedipine be used to counter low blood sugar levels in children with persistent hyperinsulinaemic hypoglycaemia? Archives of Disease in Childhood, 89, 83–85.

    PubMed  PubMed Central  Google Scholar 

  • Negus, S. (2006). Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists. Biochemical Pharmacology, 71, 1663–1670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishida, M., Sato, Y., Uemura, A., Narita, Y., Tozaki-Saitoh, H., Nakaya, M., Ide, T., Suzuki, K., Inoue, K., Nagao, T., & Kurose, H. (2008). P2Y6 receptor-Galpha12/13 signalling in cardiomyocytes triggers pressure overload-induced cardiac fibrosis. EMBO Journal, 27, 3104–3115.

    Article  CAS  Google Scholar 

  • Pathak, P., Liu, H., Boehme, S., Xie, C., Krausz, K., Gonzalez, F., & Chiang, J. (2017). Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. Journal of Biological Chemistry, 292, 11055–11069.

    Article  CAS  Google Scholar 

  • Perino, A., Pols, T., Nomura, M., Stein, S., Pellicciari, R., & Schoonjans, K. (2014). TGR5 reduces macrophage migration through mTOR induced C/EBPbeta differential translation. Journal of Clinical Investigation, 124, 5424–5436.

    Article  Google Scholar 

  • Peterson, T., Camden, J., Wang, Y., Seye, C., Wood, W., Sun, G., Erb, L., Petris, M., & Weisman, G. (2010). P2Y2 nucleotide receptor-mediated responses in brain cells. Molecular Neurobiology, 41, 356–366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Phelan, J., Jerry Reen, F., Caparros-Martin, J., O’Connor, R., & O’Gara, F. (2017). Rethinking the bile acid/gut microbiome axis in cancer. Oncotarget, 8, 115376–115747.

    Article  Google Scholar 

  • Pols, T., Nomura, M., Harach, T., Lo Sasso, G., Oosterveer, M., Thomas, C., Rizzo, G., Gioiello, A., Adorini, L., Pellicciari, R., Auwerx, J., & Schoonjans, K. (2011). TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cellular Metabolsim, 14, 747–757.

    Article  CAS  Google Scholar 

  • Pols, T., Eggink, H., & Soeters, M. (2014). TGR5 ligands as potential therapeutics in inflammatory diseases. International Journal of Interferon, Cytokine and Mediator Research, 6, 27–38.

    Article  CAS  Google Scholar 

  • Rajagopal, S., Nalli, A. D., Kumar, D. P., Bhattacharya, S., Wenhui, H., Mahavadi, S., Grider, J. R., & Murthy, K. S. (2015). Cytokine-induced S-Nitrosylation of soluble guanylyl cyclase and expression of phosphodiesterase 1A contribute to dysfunction of longitudinal smooth muscle relaxation. Journal of Pharmacology and Experimental Therapeutics, 352, 509–518.

    Article  CAS  Google Scholar 

  • Ricardo, J., Rodrigues, A., Tomé, R., & Cunha, A. (2015). ATP as a multi-target danger signal in the brain. Frontiers in Neuroscience, 9, 148.

    Google Scholar 

  • Rieg, T., Gerasimova, M., Boyer, J., Insel, P., & Vallon, V. (2011). P2Y2 receptor activation decreases blood pressure and increases renal Na+ excretion. American Journal of Physiology: Regulatory Integrative and Comparative Physiolog, 301, R510–R518.

    CAS  Google Scholar 

  • Riegel, B., Lee, C., & Dickson, V. (2011). Self care in patients with chronic heart failure. Nature Review: Cardiology, 8, 644–654.

    Google Scholar 

  • Sato, H., Antonio, M., Charles, T., Antimo, G., Mizuho, U., Hofmann, A., Régis, S., Schoonjans, K., Roberto, P., & Auwerx, J. (2008). Novel potent and selective bile acid derivatives as TGR5 agonists: Biological screening, structure-activity relationships, and molecular modeling studies. Journal of Medical Chemistry, 51, 1831–1841.

    Article  CAS  Google Scholar 

  • Schwiebert, E., Liang, L., Nai-Lin, C., Richards, W., Olteanu, D., Welty, E., & Zsembery, A. (2005). Extracellular zinc and ATP-gated P2X receptor calcium entry channels: New zinc receptors as physiological sensors and therapeutic targets. Purinergic Signalling, 1, 299–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shreiner, A., Kao, J., & Young, V. (2015). The gut microbiome in health and in disease. Current Opinion in Gateroenterology, 31, 69–75.

    Article  CAS  Google Scholar 

  • Sil, P., Wicklum, H., Surell, H., & Rada, A. (2017). Macrophage-derived IL-1β enhances monosodium urate crystal-triggered NET formation. Inflammation Research, 66, 227–237.

    Article  CAS  PubMed  Google Scholar 

  • Sriram, K., & Insel, P. (2018). G protein-coupled receptors as targets for approved drugs: How many targets and how many drugs? Molecular Pharmacology, 93, 251–258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas, C., Gioiello, A., Noriega, L., Strehle, A., Oury, J., Rizzo, G., Macchiarulo, A., Yamamoto, H., Mataki, C., Pruzanski, M., Pellicciari, R., Auwerx, J., & Schoonjans, K. (2009). TGR5-mediated bile acid sensing controls glucose homeostasis. Cellular Metabolsim, 10, 167–177.

    Article  CAS  Google Scholar 

  • Vauquelin, G., & Van Liefde, I. (2005). G protein-coupled receptors: A count of 1001 conformations. Fundamental and Clinical Pharmacology, 19, 45–56.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Y., Chen, W., Yu, D., Forman, B., & Huang, W. (2011). The g-protein coupled bile acid receptor, gpbar1 (tgr5), negatively regulates hepati inflammatory response through antagonizing nuclear factor kappa light-chain enhancer of activated b cells (nf-kappab) in mice. Hepatology, 54, 1421–1432.

    Article  CAS  PubMed  Google Scholar 

  • Wang, J., Liu, S., Nie, Y., Wu, B., Wu, Q., Song, M., Tang, M., Xiao, L., Xu, P., Tan, X., Zhang, L., Li, G., Liang, S., & Zhang, C. (2015). Activation of P2X7 receptors decreases the proliferation of murine luteal cells. Reproductive Fertilization Development, 27, 1262–1271.

    Article  CAS  Google Scholar 

  • Wang, L., Cheng, K., Li, Y., Niu, C., Cheng, J., & Niu, H. (2017). Glycyrrhizic acid increases glucagon like peptide-1 secretion via TGR5 activation in type 1-like diabetic rats. Biomedicine Pharmacotheraphy, 95, 599–604.

    Article  CAS  Google Scholar 

  • Watanabe, H., Nagesh, C., Laver, D., Seok Hwang, H., Davies, S., Roach, D., Duff, H., Roden, D., Wilde, A., & Knollmann, B. (2009). Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nature Medicine, 15, 380–383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wenker, I., Sobrinho, C., Takakura, A., Mulkey, D., & Moreira, T. (2013). P2Y1 receptors expressed by C1 neurons determine peripheral chemoreceptor modulation of breathing, sympathetic activity, and blood pressure. Hypertension, 62, 263–273.

    Article  CAS  PubMed  Google Scholar 

  • Whalen, E., Rajagopal, S., & Lefkowitz, R. (2011). Therapeutic potential of β -arrestin- and G protein-biased agonists. Trends in Molecular Medicine, 17, 126–139.

    Article  CAS  PubMed  Google Scholar 

  • Wootten, D., Christopoulos, A., & Sexton, P. (2013). Emerging paradigms in GPCR allostery: implications for drug discovery. Nature Review: Drug Discovery, 12, 630–644.

    CAS  Google Scholar 

  • Wu, L., Oshima, T., Fukui, H., Watari, J., & Miwa, I. (2017). Adenosine triphosphate induces P2Y2 activation and interleukin-8 release in human esophageal epithelial cells. Journal of Gastroenterology and Hepatology, 32, 1341–1347.

    Article  CAS  PubMed  Google Scholar 

  • Yanguas-Casás, N., Barreda-Manso, M., Nieto-Sampedro, M., & Romero-Ramírez, L. (2017). TUDCA: An Agonist of the Bile Acid Receptor GPBAR1/TGR5 With Anti-Inflammatory Effects in Microglial Cells. Journal of Cell Physiology, 232, 2231–2245.

    Article  CAS  Google Scholar 

  • Yasuto, K., Kenjiro, S., Koji, N., & Tadashi, K. (2014). The Role of MicroRNAs in Ovarian Cancer. Biomedicine Research International, 2014, 249943.

    Google Scholar 

  • Yui, S., Kanamoto, R., & Saeki, T. (2008). Deoxycholic acid can induce apoptosis in the human colon cancer cell line HCT116 in the absence of Bax. Nutrition Cancer, 60, 91–96.

    Article  CAS  PubMed  Google Scholar 

  • Zetterberg, F., & Svensson, P. (2016). State of affairs: Design and structure-activity relationships of reversible P2Y12 receptor antagonists. Bioorganic and Medicinal Chemistry Letters, 26, 2739–2754.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

    Authors and Affiliations

    1. Department of Biochemistry, Rayalaseema University, Kurnool, Andhra Pradesh, India

      Senthilkumar Rajagopal

    2. Center for Developmental Cardiology, Institute for Translational Medicine, Qingdao University, Qingdao, China

      Murugavel Ponnusamy

    Authors
    1. Senthilkumar Rajagopal
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Murugavel Ponnusamy
      View author publications

      You can also search for this author in PubMed Google Scholar

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2018 Springer Nature Singapore Pte Ltd.

    About this chapter

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this chapter

    Rajagopal, S., Ponnusamy, M. (2018). Therapeutically Targeting TGR5 and P2Y Receptors. In: Metabotropic GPCRs: TGR5 and P2Y Receptors in Health and Diseases . Springer, Singapore. https://doi.org/10.1007/978-981-13-1571-8_4

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation