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Functional coupling of M1 muscarinic acetylcholine receptor to Gαq/11 in dorsolateral prefrontal cortex from patients with psychiatric disorders: a postmortem study

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Abstract

Accumulating studies have implicated intracellular signaling through muscarinic acetylcholine receptors (mAChRs) in psychiatric illness. In the present study, carbamylcholine chloride (carbachol)-induced Gαi/o and Gαq/11 activation was identified in postmortem human prefrontal cortical membranes. The following two sample cohorts were used: subjects [1], consisting of 40 controls without neuropsychiatric disorders, and subjects [2], consisting of 20 with bipolar disorder (BP), 20 major depressive disorder (MDD), 20 schizophrenia, and 20 controls, strictly sex- and age-matched. Carbachol-stimulated [35S]GTPγS binding to human brain membranes was assessed by the two methods, i.e., conventional method using filtration techniques (Gαi/o activation coupled to M2/M4 mAChRs) applied to subjects [1], and [35S]GTPγS binding/immuno precipitation assay (Gαq/11 activation coupled to M1 mAChR) applied to subjects [1] and [2]. The concentration eliciting the half-maximal effect (EC50), maximum percent increase (%Emax), and slope factor were obtained from concentration–response curve of carbachol-induced Gαi/o and Gαq/11 activation. The pEC50 values of both carbachol-induced Gαi/o and Gαq/11 activations in subjects [1] were significantly correlated, though its implications or underlying molecular processes are unclear. The results of M1 mAChR-mediated Gαq/11 activation in subjects [2] indicated no significant disorder-specific alterations. However, the distribution patterns of the pEC50 values showed unequal variances among the groups. There was a significant inverse correlation between the %Emax values and the pEC50 values in subjects with schizophrenia, but not in those with BP or MDD, or controls. These data support the notion that schizophrenia patients consist of biologically heterogeneous subgroups with respect to M1 mAChR-mediated signaling pathways.

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Acknowledgements

This work was supported by the Saitama Medical University Internal Grant 18-B-1–03 to Y.O., the Spanish MINECO‐FEDER (SAF 2017‐88126R, SAF 2013‐48586‐R and 2011‐29918 to J.J.M., L.F.C. and J.A.G‐S., respectively) and the Basque Government (IT‐616‐13). The authors thank the collaboration of the staff members of the Basque Institute of Legal Medicine. We would like to thank Editage (www.editage.com) for English language editing.

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Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan

    Yuji Odagaki & Masakazu Kinoshita

  2. Department of Pharmacology, University of the Basque Country, UPV/EHU, 48940, Leioa, Bizkaia, Spain

    J. Javier Meana & Luis F. Callado

  3. Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Bilbao, Spain

    J. Javier Meana & Luis F. Callado

  4. Laboratory of Neuropharmacology, IUNICS/IdISPa, University of the Balearic Islands (UIB), Palma de Mallorca, Spain

    Jesús A. García-Sevilla

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  1. Yuji Odagaki
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Correspondence to Yuji Odagaki.

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Odagaki, Y., Kinoshita, M., Meana, J.J. et al. Functional coupling of M1 muscarinic acetylcholine receptor to Gαq/11 in dorsolateral prefrontal cortex from patients with psychiatric disorders: a postmortem study. Eur Arch Psychiatry Clin Neurosci 270, 869–880 (2020). https://doi.org/10.1007/s00406-019-01088-9

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