G protein-coupled receptor 35: An emerging target in inflammatory and cardiovascular disease

Frontiers in Pharmacology

Volumn 6, Issue MAR, 2015, Pages

  Divorty, Nina ^a   Mackenzie, Amanda E ^a   Nicklin, Stuart A ^a   Milligan, Graeme ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

CXCL17; GPR35; Heart failure; Hypoxia; Inflammation; Kynurenic acid; Orphan receptor; Zaprinast

Indexed keywords

AMLEXANOX; BETA ARRESTIN 2; BUFROLIN; CHEMOKINE; CHEMOKINE CXCL17; CROMOGLYCATE DISODIUM; CYCLIC GMP; DOXANTRAZOLE; EMBONIC ACID; FUROSEMIDE; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 35; GUANINE NUCLEOTIDE BINDING PROTEIN ALPHA SUBUNIT; HISTAMINE RELEASE INHIBITOR; KYNURENIC ACID; LODOXAMIDE; LYSOPHOSPHATIDIC ACID; PEMIROLAST; UNCLASSIFIED DRUG; ZAPRINAST;

AMINO ACID SUBSTITUTION; APHTHOUS ULCER; ASTHMA; AUTOIMMUNITY; CARDIOVASCULAR DISEASE; CONGESTIVE HEART FAILURE; CORONARY ARTERY DISEASE; CYTOKINE RELEASE; DRUG STRUCTURE; EDEMA; GENE EXPRESSION; GENETIC ASSOCIATION; HEART FAILURE; HUMAN; HYPERTENSION; INFLAMMATORY BOWEL DISEASE; INFLAMMATORY DISEASE; LIGAND BINDING; NOCICEPTION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIMARY SCLEROSING CHOLANGITIS; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; WRITHING TEST;

EID: 84926482061     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2015.00041     Document Type: Review

References (79)

1. Barth, M. C., Ahluwalia, N., Anderson, T. J., Hardy, G. J., Sinha, S., Alvarez-Cardona, J. A., et al. (2009). Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions. J. Biol. Chem. 284, 19189-19195. doi: 10.1074/jbc.M109.024042.
2. 2+ transients and contributes to the kynurenic acid-dependent reduction of synaptic activity at CA3-CA1 synapses. PLoS ONE 8:e82180. doi: 10.1371/journal.pone.0082180.
3. Burkhardt, A. M., Tai, K. P., Flores-Guiterrez, J. P., Vilches-Cisneros, N., Kamdar, K., Barbosa-Quintana, O., et al. (2012). CXCL17 is a mucosal chemokine elevated in idiopathic pulmonary fibrosis that exhibits broad antimicrobial activity. J. Immunol. 188, 6399-6406. doi: 10.4049/jimmunol.1102903.
4. Choi, J. H., Kim, D. H., Yun, I. J., Chang, J. H., Chun, B. G., and Choi, S. H. (2007). Zaprinast inhibits hydrogen peroxide-induced lysosomal destabilization and cell death in astrocytes. Eur. J. Pharmacol. 571, 106-115. doi: 10.1016/j.ejphar.2007.06.042.
5. Chopra, I. J., Williams, D. E., Orgiazzi, J., and Solomon, D. H. (1975). Opposite effects of dexamethasone on serum concentrations of 3, 3', 5'-triiodothyronine (reverse T3) and 3, 3'5-triiodothyronine (T3). J. Clin. Endocrinol. Metab. 41, 911-920. doi: 10.1210/jcem-41-5-911.
6. Civelli, O., Reinscheid, R. K., Zhang, Y., Wang, Z., Fredriksson, R., and Schiöth, H. B. (2013). G protein-coupled receptor deorphanizations. Annu. Rev. Pharmacol. 53, 127-146. doi: 10.1146/annurev-pharmtox-010611-134548.
7. Cosi, C., Mannaioni, G., Cozzi, A., Carlà, V., Sili, M., Cavone, L., et al. (2011). G-protein coupled receptor 35 (GPR35) activation and inflammatory pain: studies on the antinociceptive effects of kynurenic acid and zaprinast. Neuropharmacology 60, 1227-1231. doi: 10.1016/j.neuropharm.2010.11.014.
8. Deng, H., and Fang, Y. (2012). Aspirin metabolites are GPR35 agonists. Naunyn Schmiedebergs Arch. Pharmacol. 385, 729-737. doi: 10.1007/s00210-012-0752-0.
9. Deng, H., Hu, H., and Fang, Y. (2011a). Tyrphostin analogs are GPR35 agonists. FEBS Lett. 585, 1957-1962. doi: 10.1016/j.febslet.2011.05.026.
10. Deng, H., Hu, H., He, M., Hu, J., Niu, W., Ferrie, A. M., et al. (2011b). Discovery of 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3, 2-b]thiophene-2-carboxylic acid derivatives as G protein-coupled receptor 35 (GPR35) agonists. J. Med. Chem. 54, 7385-7396. doi: 10.1021/jm200999f.
11. Deng, H., Hu, H., and Fang, Y. (2012a). Multiple tyrosine metabolites are GPR35 agonists. Sci. Rep. 2, 373. doi: 10.1038/srep00373.
12. Deng, H., Hu, J., Hu, H., He, M., and Fang, Y. (2012b). Thieno[3, 2-b]thiophene-2-carboxylic acid derivatives as GPR35 agonists. Bioorg. Med. Chem. Lett. 22, 4148-4152. doi: 10.1016/j.bmcl.2012.04.057.
13. Drews, J. (2000). Drug discovery: a historical perspective. Science 287, 1960-1964. doi: 10.1126/science.287.5460.1960.
14. Ellinghaus, D., Folseraas, T., Holm, K., Ellinghaus, E., Melum, E., Balschun, T., et al. (2013). Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology 58, 1074-1083. doi: 10.1002/hep.25977.
15. Fallarini, S., Magliulo, L., Paoletti, T., de Lalla, C., and Lombardi, G. (2010). Expression of functional GPR35 in human iNKT cells. Biochem. Biophys. Res. Commun. 398, 420-425. doi: 10.1111/j.1476-5381.2012.02108.x.
16. Forrest, C. M., Gould, S. R., Darlington, L. G., and Stone, T. W. (2003). Levels of purine, kynurenine and lipid peroxidation products in patients with inflammatory bowel disease. Adv. Exp. Med. Biol. 527, 395-400. doi: 10.1007/978-1-4615-0135-0_46.
17. Friberg, L., Werner, S., Eggertsen, G., and Ahnve, S. (2002). Rapid down-regulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina? Arch. Intern. Med. 162, 1388-1394. doi: 10.1001/archinte.162.12.1388.
18. Funke, M., Thimm, D., Schiedel, A. C., and Müller, C. E. (2013). 8-Benzamidochromen-4-one-2-carboxylic acids: potent and selective agonists for the orphan G protein-coupled receptor GPR35. J. Med. Chem. 56, 5182-5197. doi: 10.1021/jm400587g.
19. Garcia-Dorado, D., Agulló, L., Sartorio, C. L., and Ruiz-Meana, M. (2009). Myocardial protection against reperfusion injury: the cGMP pathway. Thromb. Haemost. 101, 635-642. doi: 10.1160/TH08-11-0764.
20. Garland, S. L. (2013). Are GPCRs still a source of new targets? J. Biomol. Screen. 18, 947-966. doi: 10.1177/1087057113498418.
21. Gashaw, I., Ellinghaus, P., Sommer, A., and Asadullah, K. (2011). What makes a good drug target? Drug Discov. Today 17, S24-S30. doi: 10.1016/j.drudis.2011.09.007.
22. Goodman, O. B. Jr., Krupnick, J. G., Santini, F., Gurevich, V. V., Penn, R. B., Gagnon, A. W., et al. (1996). Beta-arrestin acts as a clathrin adaptor in endocytosis of the beta2-adrenergic receptor. Nature 383, 447-450. doi: 10.1038/383447a0.
23. Gotoh, M., Fujiwara, Y., Yue, J., Liu, J., Lee, S., Fells, J., et al. (2012). Controlling cancer through the autotaxin-lysophosphatidic acid receptor axis. Biochem. Soc. Trans. 40, 31-36. doi: 10.1042/BST20110608.
24. Greene, S. J., Gheorghiade, M., Borlaug, B. A., Pieske, B., Vaduganathan, M., Burnett, J. C. Jr., et al. (2013). The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction. J. Am. Heart Assoc. 2:e000536. doi: 10.1161/JAHA.113.000536.
25. Guo, J., Williams, D. J., Puhl, H. L. III, and Ikeda, S. R. (2008). Inhibition of N-Type calcium channels by activation of GPR35, an orphan receptor, heterologously expressed in rat sympathetic neurons. J. Pharmacol. Exp. Ther. 324, 352-351. doi: 10.1124/jpet.107.127266.
26. Hamilton, M. A., Stevenson, L. W., Luu, M., and Walden, J. A. (1990). Altered thyroid hormone metabolism in advanced heart failure. J. Am. Coll. Cardiol. 16, 91-95. doi: 10.1016/0735-1097(90)90462-X.
27. Heynen-Genel, S., Dahl, R., Shi, S., Sauer, M., Hariharan, S., Sergienko, E., et al. (2010). Antagonists for the Orphan Receptor GPR35. Probe Report 1 and 2. La Jolla, CA: Sanford-Burnham Centre for Chemical Genomics.
28. Heynen-Genel, S., Dahl, R., Shi, S., Sauer, M., Hariharan, S., Sergienko, E., et al. (2011). Antagonists for the Orphan Receptor GPR35. Probe Report 3. La Jolla, CA: Sanford-Burnham Centre for Chemical Genomics.
29. Hopkins, A. L., and Groom, C. R. (2002). The druggable genome. Nat. Rev. Drug Discov. 1, 727-730. doi: 10.1038/nrd892.
30. Horikawa, Y., Oda, N., Cox, N. J., Li, X., Orho-Melander, M., Hara, M., et al. (2000). Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat. Genet. 26, 163-175. doi: 10.1038/79876.
31. Hüfner, M., and Grussendorf, M. (1978). Investigations on the deiodination of thyroxine (T4) to 3, 3'-diiodothyronine (3, 3'-T 2) in rat liver homogenate. Clin. Chim. Acta 85, 243-251. doi: 10.1016/0009-8981(78)90301-7.
32. Iervasi, G., Pingitore, A., Landi, P., Raciti, M., Ripoli, A., Scarlattini, M., et al. (2003). Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 107, 708-713. doi: 10.1161/01.CIR.0000048124.64204.3F.
33. Imielinski, M., Baldassano, R. N., Griffiths, A., Russell, R. K., Annese, V., Dubinsky, M., et al. (2009). Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat. Genet. 41, 1335-1340. doi: 10.1038/ng.489.
34. Jacobson, L. H., Callander, G. E., and Hoyer, D. (2014). Suvorexant for the treatment of insomnia. Expert Rev. Clin. Pharmacol. 7, 711-730. doi: 10.1586/17512433.2014.966813.
35. Jenkins, L., Alvarez-Curto, E., Campbell, K., de Munnik, S., Canals, M., Schlyer, S., et al. (2011). Agonist activation of the G protein-coupled receptor GPR35 involves transmembrane domain III and is transduced via Ga13 and β-arrestin-2. Br. J. Pharmacol. 162, 733-748. doi: 10.1111/j.1476-5381.2010.01082.x.
36. Jenkins, L., Brea, J., Smith, N. J., Hudson, B. D., Reilly, G., Bryant, N. J., et al. (2010). Identification of novel species-selective agonists of the G-protein-coupled receptor GPR35 that promote recruitment of β-arrestin-2 and activate Ga13. Biochem. J. 432, 451-459. doi: 10.1042/BJ20101287.
37. Jenkins, L., Harries, N., Lappin, J. E., MacKenzie, A. E., Neetoo-Isseljee, Z., Southern, C., et al. (2012). Antagonists of GPR35 display high species ortholog selectivity and varying modes of action. J. Pharmacol. Exp. Ther. 343, 683-695. doi: 10.1124/jpet.112.198945.
38. Kuc, D., Zgrajka, W., Parada-Turska, J., Urbanik-Sypniewska, T., and Turski, W. A. (2008). Micromolar concentration of kynurenic acid in rat small intestine. Amino Acids 35, 503-505. doi: 10.1007/s00726-007-0631-z.
39. Lukowski, R., Krieg, T., Rybalkin, S. D., Beavo, J., and Hofmann, F. (2014). Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond. Trends Pharmacol. Sci. 35, 404-413. doi: 10.1016/j.tips.2014.05.003.
40. Luttrell, L. M., and Gesty-Palmer, D. (2010). Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol. Rev. 62, 305-330. doi: 10.1124/pr.109.002436.
41. Mackenzie, A. E., Caltabiano, G., Kent, T. C., Jenkins, L., McCallum, J. E., Hudson, B. D., et al. (2014). The antiallergic mast cell stabilizers lodoxamide and bufrolin as the first high and equipotent agonists of human and rat GPR35. Mol. Pharmacol. 85, 91-104. doi: 10.1124/mol.113.089482.
42. Mackenzie, A. E., Lappin, J. E., Taylor, D. L., Nicklin, S. A., and Milligan, G. (2011). GPR35 as a Novel Therapeutic Target. Front. Endocrinol. (Lausanne) 2:68. doi: 10.3389/fendo.2011.00068.
43. Maravillas-Montero, J. L., Burkhardt, A. M., Hevezi, P. A., Carnevale, C. D., Smit, M. J., and Zlotnik, A. (2014). Cutting edge: GPR35/CXCR8 is the receptor of the mucosal chemokine CXCL17. J. Immunol. 194, 29-33. doi: 10.4049/jimmunol.1401704.
44. Milligan, G. (2011). Orthologue selectivity and ligand bias: translating the pharmacology of GPR35. Trends Pharmacol. Sci. 32, 317-325. doi: 10.1016/j.tips.2011.02.002.
45. Min, K. D., Asakura, M., Liao, Y., Nakamaru, K., Okazaki, H., Takahashi, T., et al. (2010). Identification of genes related to heart failure using global gene expression profiling of human failing myocardium. Biochem. Biophys. Res. Commun. 393, 55-60. doi: 10.1016/j.bbrc.2010.01.076.
46. Moroni, F., Cozzi, A., Sili, M., and Mannaioni, G. (2012). Kynurenic acid: a metabolite with multiple actions and multiple targets in brain and periphery. J. Neural Transm. 119, 133-139. doi: 10.1007/s00702-011-0763-x.
47. Neetoo-Isseljee, Z., MacKenzie, A. E., Southern, C., Jerman, J., McIver, E. G., Harries, N., et al. (2013). High-throughput identification and characterization of novel, species-selective GPR35 agonists. J. Pharmacol. Exp. Ther. 344, 568-578. doi: 10.1124/jpet.112.201798.
48. Neubig, R. R. (2010). Mind your salts: when the inactive constituent isn't. Mol. Pharmacol. 78, 558-559. doi: 10.1124/mol.110.067645.
49. O'Dowd, B. F., Nguyen, T., Marchese, A., Cheng, R., Lynch, K. R., Heng, H. H., et al. (1998). Discovery of three novel G-protein-coupled receptor genes. Genomics 47, 310-313. doi: 10.1006/geno.1998.5095.
50. Ohshiro, H., Tonai-Kachi, H., and Ichikawa, K. (2008). GPR35 is a functional receptor in rat dorsal root ganglion neurons. Biochem. Biophys. Res. Commun. 365, 344-348. doi: 10.1016/j.bbrc.2007.10.197.
51. Oka, S., Ota, R., Shima, M., Yamashita, A., and Sugiura, T. (2010). GPR35 is a novel lysophosphatidic acid receptor. Biochem. Biophys. Res. Commun. 395, 232-237. doi: 10.1016/j.bbrc.2010.03.169.
52. Paluszkiewicz, P., Zgrajka, W., Saran, T., Schabowski, J., Piedra, J. L., Fedkiv, O., et al. (2009). High concentration of kynurenic acid in bile and pancreatic juice. Amino Acids 37, 637-641. doi: 10.1007/s00726-008-0183-x.
53. Prescott, R. W., Yeo, P. P., Watson, M. J., Johnston, I. D., Ratcliffe, J. G., and Evered, D. C. (1979). Total and free thyroid hormone concentrations after elective surgery. J. Clin. Pathol. 32, 321-324. doi: 10.1136/jcp.32.4.321.
54. Rancoule, C., Dusaulcy, R., Tréguer, K., Grès, S., Attané, C., and Saulnier-Blache, J. S. (2014). Involvement of autotaxin/lysophosphatidic acid signaling in obesity and impaired glucose homeostasis. Biochimie 96, 140-143. doi: 10.1016/j.biochi.2013.04.010.
55. Rask-Andersen, M., Almén, M. S., and Schiöth, H. B. (2011). Trends in the exploitation of novel drug targets. Nat. Rev. Drug Discov. 10, 579-590. doi: 10.1038/nrd3478.
56. Reilly, S. M., Chiang, S. H., Decker, S. J., Chang, L., Uhm, M., Larsen, M. J., et al. (2013). An inhibitor of the protein kinases TBK1 and IKK-e improves obesity-related metabolic dysfunctions in mice. Nat. Med. 19, 313-321. doi: 10.1038/nm.3082.
57. Ronkainen, V. P., Tuomainen, T., Huusko, J., Laidinen, S., Malinen, M., Palvimo, J. J., et al. (2014). Hypoxia-inducible factor 1-induced G protein-coupled receptor 35 expression is an early marker of progressive cardiac remodelling. Cardiovasc. Res. 101, 69-77. doi: 10.1093/cvr/cvt226.
58. Ryberg, E., Larsson, N., Sjögren, S., Hjorth, S., Hermansson, N. O., Leonova, J., et al. (2007). The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 152, 1092-1101. doi: 10.1038/sj.bjp.0707460.
59. Sams-Dodd, F. (2005). Target-based drug discovery: is something wrong? Drug. Discov. Today 10, 139-147. doi: 10.1016/S1359-6446(04)03316-1.
60. Schober, A., and Siess, W. (2012). Lysophosphatidic acid in atherosclerotic diseases. Br. J. Pharmacol. 167, 465-482. doi: 10.1111/j.1476-5381.2012.02021.x.
61. Shonberg, J., Lopez, L., Scammells, P. J., Christopoulos, A., Capuano, B., and Lane, J. R. (2014). Biased agonism at g protein-coupled receptors: the promise and the challenges-a medicinal chemistry perspective. Med. Res. Rev. 34, 1286-1330. doi: 10.1002/med.21318.
62. Siehler, S. (2009). Regulation of RhoGEF proteins by G12/13-coupled receptors. Br. J. Pharmacol. 158, 41-49. doi: 10.1111/j.1476-5381.2009.00121.x.
63. Southern, C., Cook, J. M., Neetoo-Isseljee, Z., Taylor, D. L., Kettleborough, C. A., Merritt, A., et al. (2013). Screening β-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J. Biomol. Screen. 18, 599-609. doi: 10.1177/1087057113475480.
64. Sun, Y. V., Bielak, L. F., Peyser, P. A., Turner, S. T., Sheedy, P. F. II, Boerwinkle, E., et al. (2008). Application of machine learning algorithms to predict coronary artery calcification with a sibship-based design. Genet. Epidemiol. 32, 350-360. doi: 10.1016/j.bbrc.2007.10.197.
65. Tanabe, S., Kreutz, B., Suzuki, N., and Kozasa, T. (2004). Regulation of RGS-RhoGEFs by Ga12 and Ga13 proteins. Meth. Enzymol. 390, 285-294. doi: 10.1016/S0076-6879(04)90018-3.
66. Taniguchi, Y., Tonai-Kachi, H., and Shinjo, K. (2006). Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is an agonist for GPR35. FEBS Lett. 580, 5003-5008. doi: 10.1016/j.febslet.2006.08.015.
67. Thimm, D., Funke, M., Meyer, A., and Müller, C. E. (2013). 6-Bromo-8-(4-[(3)H]methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid: a powerful tool for studying orphan G protein-coupled receptor GPR35. J. Med. Chem. 56, 7084-7099. doi: 10.1021/jm4009373.
68. Thorburn, A. N., Macia, L., and Mackay, C. R. (2014). Diet, metabolites, and "western-lifestyle" inflammatory diseases. Immunity 40, 833-842. doi: 10.1016/j.immuni.2014.05.014.
69. Thumkeo, D., Watanabe, S., and Narumiya, S. (2013). Physiological roles of Rho and Rho effectors in mammals. Eur. J. Cell. Biol. 92, 303-315. doi: 10.1016/j.ejcb.2013.09.002.
70. Ueda, H., Matsunaga, H., Olaposi, O., and Nagai, J. (2013). Lysophosphatidic acid: chemical signature of neuropathic pain. Biochim. Biophys. Acta 1831, 61-73. doi: 10.1016/j.bbalip.2012.08.014.
71. van Heerebeek, L., Hamdani, N., Falcão-Pires, I., Leite-Moreira, A. F., Begieneman, M. P., Bronzwaer, J. G., et al. (2012). Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 126, 830-839. doi: 10.1161/CIRCULATIONAHA.111.076075.
72. Venkatakrishnan, A. J., Deupi, X., Lebon, G., Tate, C. G., Schertler, G. F., and Babu, M. M. (2013). Molecular signatures of G-protein-coupled receptors. Nature 494, 185-194. doi: 10.1038/nature11896.
73. Wang, J., Simonavicius, N., Wu, X., Swaminath, G., Reagan, J., Tian, H., et al. (2006). Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J. Biol. Chem. 281, 22021-22018. doi: 10.1074/jbc.M603503200.
74. Yang, Y., Fu, A., Wu, X., and Reagan, J. D. (2012). GPR35 is a target of the loop diuretic drugs bumetanide and furosemide. Pharmacology 89, 13-17. doi: 10.1159/000335127.
75. Yang, Y., Lu, J. Y., Wu, X., Summer, S., Whoriskey, J., Saris, C., et al. (2010). G-protein-coupled receptor 35 is a target of the asthma drugs cromolyn disodium and nedocromil sodium. Pharmacology 86, 1-5. doi: 10.1159/000314164.
76. Yoon, M. H., Choi, J. I., Bae, H. B., Jeong, S. W., Chung, S. S., Yoo, K. Y., et al. (2005). Lack of the nitric oxide-cyclic GMP-potassium channel pathway for the antinociceptive effect of intrathecal zaprinast in a rat formalin test. Neurosci. Lett. 390, 114-117. doi: 10.1016/j.neulet.2005.08.006.
77. Zambrowicz, B. P., and Sands, A. T. (2003). Knockouts model the 100 best-selling drugs-will they model the next 100? Nat. Rev. Drug Discov. 2, 38-51. doi: 10.1038/nrd987.
78. Zhao, P., Lane, T. R., Gao, H. G., Hurst, D. P., Kotsikorou, E., Le, L., et al. (2014). Crucial positively charged residues for ligand activation of the GPR35 receptor. J. Biol. Chem. 289, 3625-3638. doi: 10.1074/jbc.M113.508382.
79. Zhao, P., Sharir, H., Kapur, A., Cowan, A., Geller, E. B., Adler, M. W., et al. (2010). Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity. Mol. Pharmacol. 78, 560-568. doi: 10.1124/mol.110.066746.