Serotonin 5-HT2A receptor expression and functionality in postmortem frontal cortex of subjects with schizophrenia: Selective biased agonism via Gαi1-proteins

Aintzane García-Bea; Patricia Miranda-Azpiazu; Carolina Muguruza; Sara Marmolejo-Martinez-Artesero; Rebeca Diez-Alarcia; Ane M Gabilondo; Luis F Callado; Benito Morentin; Javier González-Maeso; J Javier Meana

doi:10.1016/j.euroneuro.2019.10.013

Serotonin 5-HT_2A receptor expression and functionality in postmortem frontal cortex of subjects with schizophrenia: Selective biased agonism via G_αi1-proteins

Eur Neuropsychopharmacol. 2019 Dec;29(12):1453-1463. doi: 10.1016/j.euroneuro.2019.10.013. Epub 2019 Nov 14.

Affiliations

¹ Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain.
² Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain.
³ Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain; Biocruces Bizkaia Health Research Institute, Spain.
⁴ Biocruces Bizkaia Health Research Institute, Spain; Basque Institute of Legal Medicine, Spain.
⁵ Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, VA, USA.
⁶ Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain; Biocruces Bizkaia Health Research Institute, Spain. Electronic address: javier.meana@ehu.eus.

PMID: 31734018
DOI: 10.1016/j.euroneuro.2019.10.013

Abstract

Serotonin 5-HT_2A receptors (5-HT_2ARs) have been implicated in schizophrenia. However, postmortem studies on 5-HT_2ARs expression and functionality in schizophrenia are scarce. The 5-HT_2AR 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-HT_2AR to G-proteins was tested by measuring the activation induced by the agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride ((±)DOI) in antibody-capture [³⁵S]GTPγS scintillation proximity assays (SPA). In antipsychotic-free schizophrenia subjects, 5-HT_2AR 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. [³⁵S]GTPγS SPA revealed a significant ~6% higher stimulation of G_αi1-protein by (±)DOI in schizophrenia, whereas activation of the canonical G_αq/11-protein pathway by (±)DOI remained unchanged. Expression of G_αi1- and G_αq/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-HT_2AR mRNA expression, 5-HT_2AR protein immunoreactivity and [³H]ketanserin binding in brain cortical membranes. Overall, the data suggest a supersensitive 5-HT_2AR signaling through inhibitory G_αi1-proteins in schizophrenia. Together with previous results, a dysfunctional pro-hallucinogenic agonist-sensitive 5-HT_2AR conformation in postmortem DLPFC of subjects with schizophrenia is proposed. Atypical antipsychotic treatment would contribute to counterbalance this 5-HT_2AR supersensitivity by reducing receptor expression.

Keywords: Antipsychotics; G protein; Human brain; Schizophrenia; Serotonin 2A receptor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Frontal Lobe / drug effects
Frontal Lobe / metabolism*
Frontal Lobe / pathology
GTP-Binding Protein alpha Subunits, Gi-Go / biosynthesis*
GTP-Binding Protein alpha Subunits, Gi-Go / genetics
Gene Expression
Humans
Male
Rats
Receptor, Serotonin, 5-HT2A / biosynthesis*
Receptor, Serotonin, 5-HT2A / genetics
Schizophrenia / genetics
Schizophrenia / metabolism*
Schizophrenia / pathology
Serotonin 5-HT2 Receptor Agonists / pharmacology*
Serotonin 5-HT2 Receptor Antagonists / pharmacology

Substances

Receptor, Serotonin, 5-HT2A
Serotonin 5-HT2 Receptor Agonists
Serotonin 5-HT2 Receptor Antagonists
GTP-Binding Protein alpha Subunits, Gi-Go