Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells
| Autor: | Marie-Christine Ailhaud, Jean-Claude Martel, Nathalie Danty, Didier Cussac, Adrian Newman-Tancredi, Elisa Boutet-Robinet, Isabelle Rauly-Lestienne |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Agonist
medicine.drug_class CHO Cells Pharmacology Partial agonist Binding Competitive Antiparkinson Agents Cricetulus Cricetinae Functional selectivity medicine Animals Humans Receptor 5-HT receptor biology Chemistry 5-HT2 receptor Serotonin Receptor Agonists Lysergic Acid Diethylamide Gq alpha subunit Data Interpretation Statistical biology.protein Hallucinogens GTP-Binding Protein alpha Subunits Gq-G11 Calcium Serotonin Serotonin 5-HT2 Receptor Agonists Signal Transduction |
| Zdroj: | European journal of pharmacology. 594(1-3) |
| ISSN: | 0014-2999 |
| Popis: | Several examples of agonist-directed trafficking of receptor signalling at 5-HT2A and 5-HT2C receptors have been reported that involve independent downstream transduction pathways. We now report the functional selectivity of a series of chemically diverse agonists at human (h)5-HT2A, h5-HT2B and h5-HT2C-VSV by examining two related responses, the upstream activation of Gq/11 proteins in comparison with its associated cascade of calcium mobilisation. At the h5-HT2A receptor, d-lysergic acid diethylamide (LSD) and the antiparkinsonian agents lisuride, bromocriptine and pergolide exhibit a higher potency for Gq/11 activation than calcium release in contrast with all the other tested ligands such as 5-HT, mCPP and BW723C86, that show an opposite preference of signalling pathway. Comparable observations are made at h5-HT2B and h5-HT2C-VSV receptors, suggesting a similar mechanism of functional selectivity for the three serotonin receptors. Interestingly, the non-hallucinogenic compound lisuride behaves as a partial agonist for both Gq/11 activation and calcium release at the three 5-HT2 receptors, in contrast with DOI, LSD, pergolide and bromocriptine, which are known to provoke hallucinations, and behave as more efficacious agonists. Hence, a functional selectivity for Gq/11 activation together with a threshold of efficacy at h5-HT2A (and possibly h5-HT2B and/or h5-HT2C-VSV) may contribute to hallucinogenic liability. Thus, our results extend the notion of agonist-directed trafficking of receptor signalling to all the 5-HT2-receptor family and indicate that measures of Gq/11 activation versus calcium release may be useful to identify more effective therapeutic drugs with limited side effects. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect