Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics

Hyekyung P. Cho, Pedro M. Garcia-Barrantes, John T. Brogan, Corey R Hopkins, Colleen M. Niswender, Alice L. Rodriguez, Daryl F. Venable, Ryan D. Morrison, Michael Bubser, J. Scott Daniels, Carrie K. Jones, P. Jeffrey Conn, Craig W. Lindsley

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Abstract

(Figure Presented) Schizophrenia is a complex and highly heterogeneous psychiatric disorder whose precise etiology remains elusive. While genome-wide association studies (GWAS) have identified risk genes, they have failed to determine if rare coding single nucleotide polymorphisms (nsSNPs) contribute in schizophrenia. Recently, two independent studies identified 12 rare, deleterious nsSNPS in the GRM1 gene, which encodes the metabotropic glutamate receptor subtype 1 (mGlu1), in schizophrenic patients. Here, we generated stable cell lines expressing the mGlu1 mutant receptors and assessed their pharmacology. Using both the endogenous agonist glutamate and the synthetic agonist DHPG, we found that several of the mutant mGlu1 receptors displayed a loss of function that was not due to a loss in plasma membrane expression. Due to a lack of mGlu1 positive allosteric modulators (PAM) tool compounds active at human mGlu1, we optimized a known mGlu4 PAM/mGlu1 NAM chemotype into a series of potent and selective mGlu1 PAMs by virtue of a double "molecular switch". Employing mGlu1 PAMs from multiple chemotypes, we demonstrate that the mutant receptors can be potentiated by small molecules and in some cases efficacy restored to that comparable to wild type mGlu1 receptors, suggesting deficits in patients with schizophrenia due to these mutations may be amenable to intervention with an mGlu1 PAM. However, in wild type animals, mGlu1 negative allosteric modulators (NAMs) are efficacious in classic models predictive of antipsychotic activity, whereas we show that mGlu1 PAMs have no effect to slight potentiation in these models. These data further highlight the heterogeneity of schizophrenia and the critical role of patient selection strategies in psychiatric clinical trials to match genotype with therapeutic mechanism.

Original languageEnglish (US)
Pages (from-to)2334-2346
Number of pages13
JournalACS Chemical Biology
Volume9
Issue number10
DOIs
StatePublished - Oct 17 2014

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Modulators
Schizophrenia
Pulse amplitude modulation
Modulation
Mutation
Genes
Psychiatry
Excitatory Amino Acid Agonists
Wild Animals
Genome-Wide Association Study
Metabotropic Glutamate Receptors
Patient Selection
Antipsychotic Agents
Single Nucleotide Polymorphism
Cell membranes
Polymorphism
Genotype
Cell Membrane
Clinical Trials
Pharmacology

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Cho, H. P., Garcia-Barrantes, P. M., Brogan, J. T., Hopkins, C. R., Niswender, C. M., Rodriguez, A. L., ... Lindsley, C. W. (2014). Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics. ACS Chemical Biology, 9(10), 2334-2346. https://doi.org/10.1021/cb500560h

Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics. / Cho, Hyekyung P.; Garcia-Barrantes, Pedro M.; Brogan, John T.; Hopkins, Corey R; Niswender, Colleen M.; Rodriguez, Alice L.; Venable, Daryl F.; Morrison, Ryan D.; Bubser, Michael; Daniels, J. Scott; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.

In: ACS Chemical Biology, Vol. 9, No. 10, 17.10.2014, p. 2334-2346.

Research output: Contribution to journalArticle

Cho, HP, Garcia-Barrantes, PM, Brogan, JT, Hopkins, CR, Niswender, CM, Rodriguez, AL, Venable, DF, Morrison, RD, Bubser, M, Daniels, JS, Jones, CK, Conn, PJ & Lindsley, CW 2014, 'Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics', ACS Chemical Biology, vol. 9, no. 10, pp. 2334-2346. https://doi.org/10.1021/cb500560h
Cho, Hyekyung P. ; Garcia-Barrantes, Pedro M. ; Brogan, John T. ; Hopkins, Corey R ; Niswender, Colleen M. ; Rodriguez, Alice L. ; Venable, Daryl F. ; Morrison, Ryan D. ; Bubser, Michael ; Daniels, J. Scott ; Jones, Carrie K. ; Conn, P. Jeffrey ; Lindsley, Craig W. / Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics. In: ACS Chemical Biology. 2014 ; Vol. 9, No. 10. pp. 2334-2346.
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abstract = "(Figure Presented) Schizophrenia is a complex and highly heterogeneous psychiatric disorder whose precise etiology remains elusive. While genome-wide association studies (GWAS) have identified risk genes, they have failed to determine if rare coding single nucleotide polymorphisms (nsSNPs) contribute in schizophrenia. Recently, two independent studies identified 12 rare, deleterious nsSNPS in the GRM1 gene, which encodes the metabotropic glutamate receptor subtype 1 (mGlu1), in schizophrenic patients. Here, we generated stable cell lines expressing the mGlu1 mutant receptors and assessed their pharmacology. Using both the endogenous agonist glutamate and the synthetic agonist DHPG, we found that several of the mutant mGlu1 receptors displayed a loss of function that was not due to a loss in plasma membrane expression. Due to a lack of mGlu1 positive allosteric modulators (PAM) tool compounds active at human mGlu1, we optimized a known mGlu4 PAM/mGlu1 NAM chemotype into a series of potent and selective mGlu1 PAMs by virtue of a double {"}molecular switch{"}. Employing mGlu1 PAMs from multiple chemotypes, we demonstrate that the mutant receptors can be potentiated by small molecules and in some cases efficacy restored to that comparable to wild type mGlu1 receptors, suggesting deficits in patients with schizophrenia due to these mutations may be amenable to intervention with an mGlu1 PAM. However, in wild type animals, mGlu1 negative allosteric modulators (NAMs) are efficacious in classic models predictive of antipsychotic activity, whereas we show that mGlu1 PAMs have no effect to slight potentiation in these models. These data further highlight the heterogeneity of schizophrenia and the critical role of patient selection strategies in psychiatric clinical trials to match genotype with therapeutic mechanism.",
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