dc.contributor.author | Muneta Arrate, Itziar ![ORCID](/themes/Mirage2//images/orcid_16x16.png) | |
dc.contributor.author | Díez Alarcia, Rebeca ![ORCID](/themes/Mirage2//images/orcid_16x16.png) | |
dc.contributor.author | Horrillo Furundarena, Igor ![ORCID](/themes/Mirage2//images/orcid_16x16.png) | |
dc.contributor.author | Meana Martínez, José Javier ![ORCID](/themes/Mirage2//images/orcid_16x16.png) | |
dc.date.accessioned | 2020-08-07T07:56:38Z | |
dc.date.available | 2020-08-07T07:56:38Z | |
dc.date.issued | 2020-06-07 | |
dc.identifier.citation | European Neuropsychopharmacology 36 : 83-89 (2020) | es_ES |
dc.identifier.issn | 0924-977X | |
dc.identifier.uri | http://hdl.handle.net/10810/45907 | |
dc.description.abstract | [EN] Pimavanserin is claimed as the first antipsychotic drug that shows selectivity for serotonin 5- HT 2 receptors (5-HT 2 Rs) and lacks of affinity for dopamine D 2 receptors (D 2 Rs). Cell-based func- tional assays suggest that pimavanserin and antipsychotics with D 2 R/5-HT 2 R affinity could act as inverse agonists of 5-HT 2A Rs. However, there is not evidence of such pharmacological profile in native brain tissue. 5-HT 2A Rs are able to engage both canonical G αq/11 - and non-canonical G αi1 -proteins. In the present study, the response to pimavanserin of the 5-HT 2A R coupling to G αq/11 - and G αi1 -proteins was measured in membranes of postmortem human prefrontal cortex by antibody-capture [ 35 S]GTP γS binding scintillation proximity assays. Pimavanserin promoted a concentration-dependant inhibition of the 5-HT 2A R coupling to G αi1 -proteins whereas the re- sponse of G αq/11 -proteins was unaltered, suggesting inverse agonism and neutral antagonism properties, respectively. The inhibition was abolished in the presence of the selective 5-HT 2A R antagonist MDL-11,939 and was absent in brain cortex of 5-HT 2A R knock-out mice when com- pared to respective 5-HT 2A R wild-type animals. In conclusion, the results demonstrate the ex- istence of constitutive 5-HT 2A R activity in human brain for the signalling pathway mediated by G αi1 -proteins. Pimavanserin demonstrates 5-HT 2A R functional selectivity and exhibits inverse agonist profile towards G αi1 -proteins, which is considered the effector pathway promoting hal- lucinogenic responses. In contrast, pimavanserin behaves as neutral antagonist on the 5-HT 2A R coupling to the canonical G αq/11 -protein pathway. The results strengthen the relevance of inverse
agonism as potential mechanism of antipsychotic activity. Moreover, the existence of
functional selectivity of 5-HT 2A Rs for different G α-proteins could contribute to better design of
5-HT 2A R-related antipsychotic drugs. | es_ES |
dc.description.sponsorship | Spanish Ministry of Science, Innovation and Universities and European ERDF Funds (SAF2009-08,460 and 2017–88,126-R), and the Basque Government (IT-1211–19 and KK-2019/00- 49). The authors would like to thank the staffmembers of the Basque Institute of Legal Medicine for their cooperation in the study. IM-A was recipient of a predoctoral fellowships from the Basque Government. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.subject | serotonin 5-HT 2A receptors | es_ES |
dc.subject | antipsychotics | es_ES |
dc.subject | pimavanserin | es_ES |
dc.subject | inverse agonism | es_ES |
dc.subject | G-protein | es_ES |
dc.subject | agonist bias | es_ES |
dc.title | Pimavanserin exhibits serotonin 5-HT 2A receptor inverse agonism for G αi1 - and neutral antagonism for G αq/11 -proteins in human brain cortex | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) | es_ES |
dc.relation.publisherversion | https://www.sciencedirect.com/science/article/pii/S0924977X20301632?via%3Dihub | es_ES |
dc.identifier.doi | 10.1016/j.euroneuro.2020.05.004 | |
dc.departamentoes | Farmacología | es_ES |
dc.departamentoeu | Farmakologia | es_ES |