Antipsychotic drugs regulate hedgehog signaling by modulation of 7-dehydrocholesterol reductase levels.
Recently we identified GANT61, a small-molecule antagonist of Gli transcription factors, which are the final effectors of the mammalian Hedgehog (HH) signaling pathway. Here we describe a diamine substructure of GANT61 that carries the biological activity and show that this part of the molecule is structurally related to trans-1,4-bis(2-chlorobenzaminomethyl)cyclohexane dihydrochloride (AY9944), an inhibitor of the enzymatic activity and transcriptional inducer of 7-dehydrocholesterol-reductase (Dhcr7, EC 1.3.1.21). Treatment of cells with the GANT61 diamine, AY9944, or overexpression of DHCR7 results in the attenuation of Smoothened-dependent and -independent HH signaling. Whereas GANT61 function is independent of Dhcr7, AY9944 does require up-regulation of endogenous Dhcr7. In line with these findings, Dhcr7-modulating antipsychotic (clozapine, chlorpromazine, haloperidol) and antidepressant (imipramine) drugs regulate HH signaling in vitro and in vivo. Modulation of HH signaling may represent a hitherto undiscovered biological (side) effect of therapeutics used to treat schizophrenia and depression.
Lauth
Matthias
M
Institute of Molecular Biology and Tumor Research, Philipps University, Marburg, Germany. matthias.lauth@imt.uni-marburg.de
Rohnalter
Verena
V
Bergström
Asa
A
Kooshesh
Mahsa
M
Svenningsson
Per
P
Toftgård
Rune
R
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D003684:Dehydrocholesterols; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D044925:Oxidoreductases Acting on CH-CH Group Donors; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000071676:Zinc Finger Protein GLI1; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000494:pharmacology
D014150:Antipsychotic Agents; D003684:Dehydrocholesterols; C400551:GLI1 protein, human; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; C016705:7-dehydrocholesterol; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase