An 80-Amino Acid Deletion in the Third Intracellular Loop of a Naturally Occurring Human Histamine H3 Isoform Confers Pharmacological Differences and Constitutive Activity
| Autor: | Peter van Meer, Marlon D. Cowart, Marina Strakhova, David G. Witte, John L. Baranowski, Rob Leurs, Arthur A. Hancock, Brian R. Estvander, Gerold Bongers, Thomas R. Miller, Kathleen M. Krueger, Remko A. Bakker, Timothy A. Esbenshade |
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| Přispěvatelé: | Medicinal chemistry |
| Rok vydání: | 2007 |
| Předmět: |
Gene isoform
Molecular Sequence Data Pharmacology Biology Ligands Binding Competitive Radioligand Assay chemistry.chemical_compound SDG 3 - Good Health and Well-being GTP-Binding Proteins Cell Line Tumor Cyclic AMP Animals Humans Protein Isoforms Receptors Histamine H3 Potency Inverse agonist Amino Acid Sequence Amino Acids Cloning Molecular Receptor Sequence Deletion chemistry.chemical_classification Reverse Transcriptase Polymerase Chain Reaction Cell Membrane Brain Rats Amino acid Alternative Splicing Biochemistry chemistry Guanosine 5'-O-(3-Thiotriphosphate) Molecular Medicine Histamine H3 receptor Intracellular Histamine Protein Binding |
| Zdroj: | The Journal of Pharmacology and Experimental Therapeutics, 323(3), 888-98. American Society for Pharmacology and Experimental Therapeutics Bongers, G M, Krueger, K M, Miller, T R, Baranowski, J L, Estvander, B R, Witte, D G, Strakhova, M I, van der Meer, P, Bakker, R A, Cowart, M D, Hancock, A A, Esbenshade, T A & Leurs, R 2007, ' An 80-amino acid deletion in the third intracellular loop of a naturally occurring human histamine H3 isoform confers pharmacological differences and constitutive activity ', The Journal of Pharmacology and Experimental Therapeutics, vol. 323, no. 3, pp. 888-98 . https://doi.org/10.1124/jpet.107.127639 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | In this article, we pharmacologically characterized two naturally occurring human histamine H3 receptor (hH3R) isoforms, hH3R(445) and hH3R(365). These abundantly expressed splice variants differ by a deletion of 80 amino acids in the intracellular loop 3. In this report, we show that the hH3R(365) is differentially expressed compared with the hH3R(445) and has a higher affinity and potency for H3R agonists and conversely a lower potency and affinity for H3R inverse agonists. Furthermore, we show a higher constitutive signaling of the hH3R(365) compared with the hH3R(445) in both guanosine-5'-O-(3-[35S]thio) triphosphate binding and cAMP assays, likely explaining the observed differences in hH3R pharmacology of the two isoforms. Because H3R ligands are beneficial in animal models of obesity, epilepsy, and cognitive diseases such as Alzheimer's disease and attention deficit hyperactivity disorder and currently entered clinical trails, these differences in H3R pharmacology of these two isoforms are of great importance for a detailed understanding of the action of H3R ligands. |
| Databáze: | OpenAIRE |
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