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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice
Michael C Wehr1, Wilko Hinrichs2, Magdalena M Brzózka3
1Molecular and Behavioral Neurobiology, Department of Psychiatry, Ludwig Maximilian University of Munich, Munich, Germany michael.wehr@med.uni-muenchen.de moritz.rossner@med.uni-muenchen.de.
Abstract:
Enhanced NRG1-ERBB4 signaling is a risk pathway in schizophrenia, and corresponding mouse models display several endophenotypes of the disease. Nonetheless, pathway-directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell-based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1-ERBB4 signaling for repurposing. We recovered spironolactone, known as antagonist of corticosteroids, as an inhibitor of the ERBB4 receptor and tested it in pharmacological and biochemical assays to assess secondary compound actions. Transgenic mice overexpressing Nrg1 type III display cortical Erbb4 hyperphosphorylation, a condition observed in postmortem brains from schizophrenia patients. Spironolactone treatment reverted hyperphosphorylation of activated Erbb4 in these mice. In behavioral tests, spironolactone treatment of Nrg1 type III transgenic mice ameliorated schizophrenia-relevant behavioral endophenotypes, such as reduced sensorimotor gating, hyperactivity, and impaired working memory. Moreover, spironolactone increases spontaneous inhibitory postsynaptic currents in cortical slices supporting an ERBB4-mediated mode-of-action. Our findings suggest that spironolactone, a clinically safe drug, provides an opportunity for new treatment options for schizophrenia.
Insights
Spironolactone, an existing drug, effectively targets the NRG1-ERBB4 pathway implicated in schizophrenia. This study shows spironolactone ameliorates schizophrenia-like behaviors in mice by normalizing ERBB4 signaling.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Enhanced Neuregulin 1 (NRG1)-ERBB4 signaling is a risk pathway in schizophrenia.
- Mouse models of schizophrenia exhibit endophenotypes linked to this pathway, but effective treatments remain elusive.
Purpose of the Study:
- To identify clinically applicable compounds that modulate NRG1-ERBB4 signaling for potential schizophrenia treatment.
- To repurpose existing drugs for novel therapeutic applications in schizophrenia.
Main Methods:
- A cell-based assay utilizing split TEV technology screened a library of clinically approved compounds.
- Spironolactone was identified as an ERBB4 receptor inhibitor and further tested in pharmacological and biochemical assays.
- Transgenic mice overexpressing Nrg1 type III were used to model schizophrenia endophenotypes.
Main Results:
- Spironolactone treatment reverted Erbb4 hyperphosphorylation in Nrg1 type III transgenic mice, mirroring findings in schizophrenia patient brains.
- Spironolactone ameliorated schizophrenia-relevant behavioral deficits in mice, including sensorimotor gating, hyperactivity, and working memory impairments.
- Biochemical assays confirmed an ERBB4-mediated mechanism of action, with spironolactone increasing inhibitory postsynaptic currents.
Conclusions:
- Spironolactone, a clinically safe drug, demonstrates potential as a novel therapeutic agent for schizophrenia by targeting the NRG1-ERBB4 pathway.
- Drug repurposing of spironolactone offers a promising avenue for developing new treatment options for schizophrenia patients.
