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.

Article Details

Citation

Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, Rauly-Lestienne I

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.

Eur J Pharmacol. 2008 Oct 10;594(1-3):32-8. doi: 10.1016/j.ejphar.2008.07.040. Epub 2008 Jul 30.

PubMed ID
18703043 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Bromocriptine5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Agonist
Details
Bromocriptine5-hydroxytryptamine receptor 2BProteinHumans
Unknown
Agonist
Details
Bromocriptine5-hydroxytryptamine receptor 2CProteinHumans
Unknown
Agonist
Details
Pergolide5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Agonist
Details
Pergolide5-hydroxytryptamine receptor 2BProteinHumans
Unknown
Agonist
Details
Pergolide5-hydroxytryptamine receptor 2CProteinHumans
Unknown
Agonist
Details
Polypeptides
NameUniProt ID
5-hydroxytryptamine receptor 2BP41595Details
5-hydroxytryptamine receptor 2AP28223Details
5-hydroxytryptamine receptor 2CP28335Details