p11, through unknown mechanisms, is required for behavioral and cellular responses to selective serotonin reuptake inhibitors (SSRIs). We show that SMARCA3, a chromatin-remodeling factor, is a target for the p11/annexin A2 heterotetrameric complex. Determination of the crystal structure indicates that SMARCA3 peptide binds to a hydrophobic pocket in the heterotetramer. Formation of this complex increases the DNA-binding affinity of SMARCA3 and its localization to the nuclear matrix fraction. In the dentate gyrus, both p11 and SMARCA3 are highly enriched in hilar mossy cells and basket cells. The SSRI fluoxetine induces expression of p11 in both cell types and increases the amount of the ternary complex of p11/annexin A2/SMARCA3. SSRI-induced neurogenesis and behavioral responses are abolished by constitutive knockout of SMARCA3. Our studies indicate a central role for a chromatin-remodeling factor in the SSRI/p11 signaling pathway and suggest an approach to the development of improved antidepressant therapies. PaperClip:
Bibliographical noteFunding Information:
This work was supported by DOD/USAMRAA Grant W81XWH-09-1-0392 to Y.K.; DOD/USAMRAA Grant W81XWH-09-1-0402 to P. Greengard; the JPB Foundation to P. Greengard; the Fisher Center Foundation to P. Greengard; NIH grants (MH090963, DA10044, and AG09464) to Y.K. and P. Greengard; and the Maloris Foundation and the Abby Rockefeller Mauze Trust to D.J.P. We thank the staff at beamline 24ID-C of the Advanced Photon Source at the Argonne National Laboratory and beamline X29 of the National Synchrotron Light Source at the Brookhaven National Laboratory for assistance with data collection. We thank Daesoo Kim, Eric Schmidt, Jennifer Wagner-Schmidt, and Yotam Sagi for their helpful advice and discussion, and Elisabeth Griggs for technical assistance. We would like to thank Ji-Eun Kim for the mass spectrometry analysis. Finally, we would like to acknowledge Rada Norinsky and the Rockefeller University Transgenics Services Laboratory for their excellent IVF services; and Henry Zebroski III and Nagarajan Chandramouli from The Rockefeller University Proteomics Resource Center.