title: CRTC1 nuclear localization in the hippocampus of the pilocarpine-induced status epilepticus model of temporal lobe epilepsy.
abstract: cAMP response-element binding protein (CREB)-dependent genes are differentially expressed in brains of temporal lobe epilepsy (TLE) patients and also in animal models of TLE. Previous studies have demonstrated the importance of CREB regulated transcription in TLE. However, the role of the key regulator of CREB activity, CREB-regulated transcription coactivator 1 (CRTC1), has not been explored in epilepsy. In the present study the pilocarpine-induced status epilepticus (SE) model of TLE was used to study the regulation of CRTC1 during and following SE. Nuclear translocation of CRTC1 is critical for its transcriptional activity, and dephosphorylation at serine 151 residue via calcineurin phosphatase regulates cytoplasmic to nuclear transit of CRTC1. Here, we examined the localization and phosphorylation (Ser151) of CRTC1 in SE-induced rat hippocampus at two different time points after SE onset. One hour after SE onset, we found that CRTC1 translocates to the nucleus of CA1 neurons but not CA3 or dentate granule neurons. We further found that this CRTC1 nuclear localization is independent of Ser151 dephosphorylation since we did not detect any difference in dephosphorylation of Ser151 between control and SE animals at this time point. In contrast, 48 h after SE CRTC1 shows increased nuclear localization in the dentate gyrus (DG) of the SE-induced rats. At 48 h after SE, FK506 treatment blocked CRTC1 nuclear localization and dephosphorylation of Ser151. Our results provide evidence that CREB cofactor CRTC1 translocates into the nucleus of a distinct subset of hippocampal neurons during and following SE and this translocalization is regulated by calcineurin at a later time point following SE. Nuclear CRTC1 can bind to CREB possibly altering transcription during epileptogenesis.
authors: Department of Neurology, School of Medicine, Stanford University, 1201 Welch Road, P211 MSLS, Stanford, CA 94305, United States.
authors: D
authors: D
authors: Dubey
authors: Stanford University Medical School, P211 MSLS, 1201 Welch Road, Stanford, CA 94305, United States. Electronic address: brenda2@stanford.edu.
authors: B E
authors: BE
authors: Porter
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D003292:Convulsants / Q000633:toxicity; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013226:Status Epilepticus / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D003292:Convulsants; C519510:Crtc1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D010862:Pilocarpine
keywords: CREB; CRTC1; FK506; calcineurin; epilepsy; status epileptics