Functional activation of Gαq coupled to 5-HT2A receptor and M1 muscarinic acetylcholine receptor in postmortem human cortical membranes View Full Text


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Article Info

DATE

2017-07-07

AUTHORS

Yuji Odagaki, Masakazu Kinoshita, Toshio Ota, J. Javier Meana, Luis F. Callado, Jesús A. García-Sevilla

ABSTRACT

Heterotrimeric guanine nucleotide-binding proteins (G-proteins) play a pivotal role in a wide range of signal transduction pathways, and receptor/G-protein coupling has been implicated in the pathophysiology of mental disorders. In this study, guanosine-5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding/immunoprecipitation assay for Gαq was applied to postmortem human brains. After its optimization for human prefrontal cortical membranes, we selected 5-hydroxytryptamine (5-HT) and carbachol as efficient agonists for subsequent experiments. The concentration–response curve of 5-HT shifted towards the right by the addition of increasing concentrations of ketanserin (with a pA2 value of 9.18), indicating the involvement of the 5-HT2A receptor. Besides, the carbachol-stimulated [35S]GTPγS binding to Gαq was competitively antagonized by telenzepine (with a pA2 value of 8.81), indicating the involvement of the M1 muscarinic acetylcholine receptor (mAChR). Concentration–response curves of 5-HT2A receptor- and M1 mAChR-mediated Gαq activation were determined in 40 subjects. The mean maximum percentage increase (%Emax) was 155 and 470%, respectively, and the mean half-maximal effect concentration (EC50) was 131 nM and 15.2 µM, respectively. When the pharmacological parameters were correlated with age, postmortem delay, freezing storage period, and tissue pH, no statistically significant correlation was observed except for the negative correlation between age and %Emax value of carbachol-stimulated [35S]GTPγS binding to Gαq. The %Emax values for 5-HT2A receptor- and M1 mAChR-mediated Gαq activation also tended to correlate with each other. These results provide fundamental information of Gαq-coupled 5-HT2A receptor and M1 mAChR in native human brains, and lay the foundation for future studies in mental disorder patients. More... »

PAGES

1123-1133

References to SciGraph publications

  • 2009-04-29. Altered M1 Muscarinic Acetylcholine Receptor (CHRM1)-Gαq/11 Coupling in a Schizophrenia Endophenotype in NEUROPSYCHOPHARMACOLOGY
  • 2014-07-10. How much do we know about the coupling of G-proteins to serotonin receptors? in MOLECULAR BRAIN
  • 2013-06-09. Pharmacological characterization of M1 muscarinic acetylcholine receptor-mediated Gq activation in rat cerebral cortical and hippocampal membranes in NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY
  • 2004-07-30. Pharmacological characterisation of the agonist radioligand binding site of 5-HT2A, 5-HT2B and 5-HT2C receptors in NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY
  • 2000-04. Sex-related differences in the muscarinic acetylcholinergic receptor in the healthy human brain —A positron emission tomography study— in ANNALS OF NUCLEAR MEDICINE
  • 2003-12-29. Impairment of Gsα function in human brain cortex of Alzheimer’s disease: comparison with normal aging in JOURNAL OF NEURAL TRANSMISSION
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  • 1996-11. 5-HT receptors in mammalian brain: receptor autoradiography andin situ hybridization studies of new ligands and newly identified receptors in JOURNAL OF MOLECULAR HISTOLOGY
  • 2011-11-30. Muscarinic acetylcholine receptor-mediated activation of Gq in rat brain membranes determined by guanosine-5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding using an anti-G protein scintillation proximity assay in JOURNAL OF NEURAL TRANSMISSION
  • 2002-12-01. Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia in MOLECULAR PSYCHIATRY
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    http://scigraph.springernature.com/pub.10.1007/s00702-017-1749-0

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    http://dx.doi.org/10.1007/s00702-017-1749-0

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28687907


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    34 schema:description Heterotrimeric guanine nucleotide-binding proteins (G-proteins) play a pivotal role in a wide range of signal transduction pathways, and receptor/G-protein coupling has been implicated in the pathophysiology of mental disorders. In this study, guanosine-5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding/immunoprecipitation assay for Gαq was applied to postmortem human brains. After its optimization for human prefrontal cortical membranes, we selected 5-hydroxytryptamine (5-HT) and carbachol as efficient agonists for subsequent experiments. The concentration–response curve of 5-HT shifted towards the right by the addition of increasing concentrations of ketanserin (with a pA2 value of 9.18), indicating the involvement of the 5-HT2A receptor. Besides, the carbachol-stimulated [35S]GTPγS binding to Gαq was competitively antagonized by telenzepine (with a pA2 value of 8.81), indicating the involvement of the M1 muscarinic acetylcholine receptor (mAChR). Concentration–response curves of 5-HT2A receptor- and M1 mAChR-mediated Gαq activation were determined in 40 subjects. The mean maximum percentage increase (%Emax) was 155 and 470%, respectively, and the mean half-maximal effect concentration (EC50) was 131 nM and 15.2 µM, respectively. When the pharmacological parameters were correlated with age, postmortem delay, freezing storage period, and tissue pH, no statistically significant correlation was observed except for the negative correlation between age and %Emax value of carbachol-stimulated [35S]GTPγS binding to Gαq. The %Emax values for 5-HT2A receptor- and M1 mAChR-mediated Gαq activation also tended to correlate with each other. These results provide fundamental information of Gαq-coupled 5-HT2A receptor and M1 mAChR in native human brains, and lay the foundation for future studies in mental disorder patients.
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