Serotonin 5-HT2A receptor expression and functionality in postmortem frontal cortex of subjects with schizophrenia: Selective biased agonism via Gαi1-proteins
| Autor: | Carolina Muguruza, Aintzane García-Bea, Luis F. Callado, Rebeca Diez-Alarcia, Patricia Miranda-Azpiazu, Benito Morentin, Sara Marmolejo-Martinez-Artesero, Javier González-Maeso, Ane M. Gabilondo, J. Javier Meana |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_specialty
Postmortem studies Ketanserin binding medicine.drug_class Receptor expression Atypical antipsychotic 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Haloperidol g protein Pharmacology (medical) human brain Biological Psychiatry Clozapine Pharmacology lysergic-acid diethylamide prefrontal cortex business.industry serotonin 2a receptor Human brain 030227 psychiatry Dorsolateral prefrontal cortex schizophrenia Psychiatry and Mental health antipsychotics messenger-rna expression modulation medicine.anatomical_structure Endocrinology Neurology 2a receptor depression responses Neurology (clinical) business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Addi. Archivo Digital para la Docencia y la Investigación instname |
| ISSN: | 2009-0846 |
| Popis: | Serotonin 5-HT2A receptors (5-HT(2A)Rs) have been implicated in schizophrenia. However, postmortem studies on 5-HT(2A)Rs expression and functionality in schizophrenia are scarce. The 5-HT2AR mRNA and immunoreactive protein expression were evaluated in postmortem tissue from dorsolateral prefrontal cortex (DLPFC) of antipsychotic-free (n = 18) and antipsychotic-treated (n = 9) subjects with schizophrenia, and matched controls (n = 27). Functional coupling of 5-HT2AR to G-proteins was tested by measuring the activation induced by the agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride ((+/-)DOI) in antibody-capture [S-35]GTP gamma S scintillation proximity assays (SPA). In antipsychotic-free schizophrenia subjects, 5-HT2AR mRNA expression and protein immunoreactivity in total homogenates was similar to controls. In contrast, in antipsychotic-treated schizophrenia subjects, lower mRNA expression (60 +/- 9% vs controls) and a trend to reduced protein immunoreactivity (86 +/- 5% vs antipsychotic-free subjects) just in membrane-enriched fractions was observed. [S-35]GTP gamma S SPA revealed a significant (similar to)6% higher stimulation of G(alpha i1)-protein by (+/-)DOI in schizophrenia, whereas activation of the canonical G(alpha q/11)-protein pathway by (+/-)DOI remained unchanged. Expression of G(alpha i1) - and G(alpha q/11)-proteins did not differ between groups. Accordingly, in rats chronically treated with clozapine, but not with haloperidol, a 30-40% reduction was observed in 5-HT2AR mRNA expression, 5-HT2AR protein immunoreactivity and [H-3]ketanserin binding in brain cortical membranes. Overall, the data suggest a supersensitive 5-HT2AR signaling through inhibitory G(alpha i1)-proteins in schizophrenia. Together with previous results, a dysfunctional pro-hallucinogenic agonist-sensitive 5-HT2AR conformation in postmortem DLPFC of subjects with schizophrenia is proposed. Atypical antipsychotic treatment would contribute to counterbalance this 5-HT2AR supersensitivity by reducing receptor expression. (C) 2019 The Author(s). Published by Elsevier B.V. This study was supported by US National Institutes of Health (NIH) (R01 MH084894 and R01MH111940 to JG-M), Spanish Ministry of Science, Innovation and Universities and European ERDF Funds (SAF2009-08460 and 2017-88126-R to JJM), and the Basque Government (IT-616-13 and IT-1211-19 to JJM). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|