By a News Reporter-Staff News Editor at Biotech Week -- Fresh data on Ethylamines are presented in a new report. According to news originating from Uttar Pradesh, India, by NewsRx correspondents, research stated, "The synthetic nuclear bile acid receptor (farnesoid X receptor [FXR]) agonist GW4064 is extensively used as a specific pharmacological tool to illustrate FXR functions. We noticed that GW4064 activated empty luciferase reporters in FXR-deficient HEK-293T cells."
Our news journalists obtained a quote from the research from Central Drug Research Institute, "We postulated that this activity of GW4064 might be routed through as yet unknown cellular targets and undertook an unbiased exploratory approach to identify these targets. Investigations revealed that GW4064 activated cAMP and nuclear factor for activated T-cell response elements (CRE and NFAT-RE, respectively) present on these empty reporters. Whereas GW4064-induced NFAT-RE activation involved rapid intracellular Ca2+ accumulation and NFAT nuclear translocation, CRE activation involved soluble adenylyl cyclase-dependent cAMP accumulation and Ca2+-calcineurin-dependent nuclear translocation of transducers of regulated CRE-binding protein 2. Use of dominant negative heterotrimeric G-protein minigenes revealed that GW4064 caused activation of G alpha(i/o) and G(q/11) G proteins. Sequential pharmacological inhibitor-based screening and radioligand-binding studies revealed that GW4064 interacted with multiple G protein-coupled receptors. Functional studies demonstrated that GW4064 robustly activated H1 and H4 and inhibited H2 histamine receptor signaling events. We also found that MCF-7 breast cancer cells, reported to undergo GW4064-induced apoptosis in an FXR-dependent manner, did not express FXR, and the GW4064-mediated apoptosis, also apparent in HEK-293T cells, could be blocked by selective histamine receptor regulators."
According to the news editors, the research concluded: "Taken together, our results demonstrate identification of histamine receptors as alternate targets for GW4064, which not only necessitates cautious interpretation of the biological functions attributed to FXR using GW4064 as a pharmacological tool but also provides a basis for the rational designing of new pharmacophores for histamine receptor modulation."
For more information on this research see: Synthetic FXR Agonist GW4064 Is a Modulator of Multiple G Protein-Coupled Receptors. Molecular Endocrinology, 2014;28(5):659-673. Molecular Endocrinology can be contacted at: Endocrine Soc, 2055 L St NW, Suite 600, Washington, DC 20036, USA. (The Endocrine Society - www.endo-society.org/; Molecular Endocrinology - mend.endojournals.org/)
The news correspondents report that additional information may be obtained from N. Singh, CSIR, Cent Drug Res Inst, Div Mol & Struct Biol, Lucknow 226031, Uttar Pradesh, India. Additional authors for this research include M. Yadav, A.K. Singh, H. Kumar, S.K.D. Dwivedi, J.S. Mishra, A. Gurjar, A. Manhas, S. Chandra, P.N. Yadav, K. Jagavelu, M.I. Siddiqi, A.K. Trivedi, N. Chattopadhyay and S. Sanyal (see also Ethylamines).
Keywords for this news article include: Asia, India, Therapy, Autacoids, Ethylamines, Pharmacology, Uttar Pradesh, Membrane Proteins, Biogenic Monoamines, Histamine Receptors, Cell Surface Receptors, Biogenic Amine Receptors, G-Protein-Coupled Receptors
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