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.
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.
Cussac
Didier
D
Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, F 81106 Castres Cedex, France. didier.cussac@pierre-fabre.com
Boutet-Robinet
Elisa
E
Ailhaud
Marie-Christine
MC
Newman-Tancredi
Adrian
A
Martel
Jean-Claude
JC
Danty
Nathalie
N
Rauly-Lestienne
Isabelle
I
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D003627:Data Interpretation, Statistical; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006213:Hallucinogens / Q000494:pharmacology; D006801:Humans; D008238:Lysergic Acid Diethylamide / Q000031:analogs & derivatives / Q000494:pharmacology; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000978:Antiparkinson Agents; D006213:Hallucinogens; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D008238:Lysergic Acid Diethylamide; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium