Expression of the neurotrophin receptor trkB is regulated by the cAMP/CREB pathway in neurons

Deogracias, Rubén; Espliguero, Gemma; Iglesias, Teresa; Rodrı́guez-Peña, Angeles

doi:10.1016/j.mcn.2004.03.007

Cited by 87 publications

(59 citation statements)

References 41 publications

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“…We (Kingsbury et al, 2003) and others (Deogracias et al, 2004) have shown that P2 TRKBluciferase reporters can also be stimulated cAMP signaling induced by forskolin. The requirement for TCaRE3 in mediating P2 induction following forskolin treatment was tested using the TRKB-luciferase constructs generated to map TCaRE3.…”

Section: Tcare3 Is Also Required For Camp Responsiveness Of Trkb P2mentioning

confidence: 81%

“…How the activation of CREB by specific intracellular signals or in different cell types translates to distinct gene activation patterns remains largely unknown and will require the systematic analysis of CREB-dependent activation of many genes in order to identify common themes (Conkright et al, 2003). Although the promoters of a number of CREB-dependent genes, including cFos and BDNF, have been shown to contain additional regulatory elements that impose specificity on CREB-mediated responses, our understanding of the TRKB promoter elements that function to shape the transcriptional response to Ca 2+ and cAMP has been limited to the role of the tandem CREs (TCaRE2) (Kingsbury et al, 2003;Deogracias et al, 2004). …”

Section: Discussionmentioning

confidence: 99%

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Ca2+, CREB and krüppel: A novel KLF7-binding element conserved in mouse and human TRKB promoters is required for CREB-dependent transcription

Kingsbury

Krueger

2007

Molecular and Cellular Neuroscience

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Brain-derived neurotrophic factor (BDNF) signaling through its receptor, trkB, is essential for the proper development and function of the nervous system. Here we identify a novel regulatory element designated TCaRE3 (TRKB Ca 2+ Response Element 3) required for CREB-dependent TRKB transcription in neurons. TCaRE3-inactivating mutations abolished both Ca 2+ -and cAMP-stimulated TRKB expression, despite the presence of upstream CREs. TCaRE3 mutations also reduced basal expression by at least 80%. Electrophoretic mobility shift assays revealed the presence of a neuronal nuclear factor able to bind TCaRE3 in a sequence-specific manner and we have identified krüppel-like factor 7 (KLF7) as a candidate TCaRE3 transcription factor. Importantly, despite limited overall sequence homology between the promoter regions of the human and mouse TRKB genes, TCaRE3 exhibits 100% sequence identity. Mutation analysis of the human TRKB promoter region demonstrated that the role of TCaRE3 is also conserved, suggesting that the functional interaction between CREB bound to the CREs and KLF7 bound to TCaRE3 is essential for the proper regulation of TRKB in neurons.The neurotrophin, BDNF, signals through its receptor trkB to mediate neuron survival and differentiation, neurite outgrowth, axon guidance, and activity-dependent synaptic plasticity (for reviews, see Huang and Reichardt, 2001;. Studies of mice with forebrain-targeted deletions in the genes coding for BDNF or trkB displayed defects in neuron survival, long term potentiation, and learning and memory (Korte et al., 1996;Patterson et al., 1996;Xu et al., 2000). Abnormal BDNF/trkB signaling has been linked to neurological and psychiatric disorders such as Alzheimer's and Parkinson's diseases (Ferrer et al., 1999;Allen et al., 1999;Murer et al., 2001;Holsinger et al., 2000; Fumagalli et al., 2006a,b), as well as depression and schizophrenia (Nestler et al., 2002;Angelucci et al., 2005;Hashimoto et al., 2004;).The expression of BDNF in cultured cortical neurons is upregulated by depolarization (Ghosh et al., 1994) due to the activation of Ca 2+ -dependent regulatory promoter elements in BDNF, the gene encoding BDNF (Tao et al., 1998;Shieh et al., 1998). Similarly, we demonstrated that depolarization-induced Ca 2+ signaling specifically stimulated expression of catalyticallyactive, full-length trkB without affecting the inactive, truncated (T1) isoform (Kingsbury et al., 2003). The increased full-length trkB was readily auto-phosphorylated in response to Address correspondence to: Bruce K. Krueger, Department of Physiology, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD 21201, Tel. 410 706-5065; Fax: 410 706-8341; E-mail: bkrueger@umaryland.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is publishe...

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Section: Tcare3 Is Also Required For Camp Responsiveness Of Trkb P2mentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Ca2+, CREB and krüppel: A novel KLF7-binding element conserved in mouse and human TRKB promoters is required for CREB-dependent transcription

Kingsbury

Krueger

2007

Molecular and Cellular Neuroscience

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“…Classically in neurons, PKA phosphorylates the transcription factor CREB to increase expression of cell survival genes such as BDNF and the anti-apoptotic protein bcl-2 (Freeland et al, 2001, Tabuchi et al, 2002, Deogracias et al, 2004, Meller et al, 2005. Previous studies have reported that CREB is activated after TBI and BDNF levels are elevated as well (Dash et al, 1995, Yang et al, 1996, Hicks et al, 1997, Truettner et al, 1999, Griesbach et al, 2004a, Griesbach et al, 2004b, Hu et al, 2004.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

134

151

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Traumatic brain injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated by the inflammatory response and progress from hours to days after the initial injury. Using a clinically relevant model of TBI, the parasagittal fluid-percussion brain injury (FPI) model, we found injury-induced impairments in the cyclic AMP (cAMP) signaling pathway. Levels of cAMP were depressed in the ipsilateral parietal cortex and hippocampus, as well as activation of its downstream target, protein kinase A, from 15 min to 48 hr after moderate FPI. To determine if preventing hydrolysis of cAMP by administration of a phosphodiesterase (PDE) IV inhibitor would improve outcome after TBI, we treated animals intraperitoneally with rolipram (0.3 or 3.0 mg/kg) 30 min prior to TBI, and then once per day for three days. Rolipram treatment restored cAMP to sham levels and significantly reduced cortical contusion volume and improved neuronal cell survival in the parietal cortex and CA3 region of the hippocampus. Traumatic axonal injury, characterized by β-amyloid precursor protein deposits in the external capsule, was also significantly reduced in rolipramtreated animals. Furthermore, levels of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased with rolipram treatment. These results demonstrate that the cAMP-PKA signaling cascade is downregulated after TBI, and that treatment with a PDE IV inhibitor improves histopathological outcome and decreases inflammation after TBI. Keywordscamp; Fluid-percussion; Inflammation; Interleukin-1β; PKA; Phosphodiesterase; Rolipram; TNF-α; Traumatic brain injury; TBI Traumatic brain injury (TBI) is a prevalent, debilitating health problem, occurring in 1.4 million people each year and disabling 5 million people in the United States (Langlois et al., 2004). The subsequent progressive injury after brain trauma develops from hours to days after the initiating insult, providing an accessible time window for pharmacological therapies. Despite Address correspondence to: W. Dalton Dietrich, Scientific Director, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, P.O. Box 016960, (R-48), Miami, FL 33101, E-mail: ddietrich@miami.edu, Phone: 305-243-2297, Fax: 305-243-3207. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Brain trauma results in contusion formation, neuronal apoptosis, and axonal tract damage. These pathologies are worsened by the inflammatory cascade set into motion by the initial injury (Morganti-Kossmann et al., 2002. Two pro-i...

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“…(26) For example, our research group has shown that, relative to normal controls, certain depressed patients have deficient PKA and PKC protein levels,(27;28) lower binding of cyclic AMP to PKA,(29) reduced phosphorylation of CREB, (29) and altered gene expression patterns; (30) (6;7;7;31-39) This decrease in the activity of these two key enzymes would be expected to alter the expression of genes that contain CRE elements in their promoters; these would include key proteins that regulate the stress response in brain, including brain derived neurotrophic factor (BDNF), (40)(41)(42)) the BDNF receptor trk-b, (43) and glucocorticoid receptors (GR). (44) Moreover, GR functions as a transcriptional factor and regulates the expression of other genes, specifically exerting an inhibitory effect on corticotrophin releasing hormone (CRH).…”

Section: Intracellular Signal Transductionmentioning

confidence: 99%

The Molecular Neurobiology of Depression

Shelton

2007

Psychiatric Clinics of North America

128

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The molecular neurobiology of depression begins with an idea: depressive disorders represent a family of related but distinct conditions. Different points of vulnerability in the brain may predispose to depressive disorders. For example, it is likely that the core pathophysiology of depression associated with early life adversity is different from non-trauma related disorders. In particular, the pathophysiology of trauma-related depression involves the hypothalamic-pituitary-adrenal (HPA) axis, although, in turn, this reflects underlying molecular etiologies. In particular, dysregulation of signal transduction mechanisms may be one site of origin. This may be the result of yet other processes such as the effects of reactive oxygen species (ROS) or genomic imprinting. Unraveling these complex causes may lead to novel treatments that can be used in a targeted fashion. Keywords/phrasesDepression; molecular; signal transduction; gene expression; genomics Unipolar depressive disorders encompass a range of features that strongly suggest a neurobiological substrate. These include symptoms such as include sleep and appetite disturbances (both up and down), loss of interest and pleasure, negative rumination, fatigue, and poor concentration, but also apparent abnormalities of the hypothalamic-pituitary-adrenal axis(1) or of neuroplasticity.(2) Moreover, depression appears to have genetic antecedents, which also point to a biological contribution to etiology.(3) However, the exact pathophysiology has been largely unknown until the last decade or so.To begin, depression clearly is not one entity, but subsumes a range of causes that involve genetic contributors, along with early and later stress.(2;4) Therefore, the depressive spectrum include conditions related to early traumatic events (typically with early onset of depression as well), through episodes in the absence of early trauma that may or may not be precipitated by an acute stressor. Therefore, the heterogeneous nature of the condition must be taken into account in any search for a biological substrate.Unfortunately, that is not usually the case. In fact, most studies simply take an unselected groups of "depressed" and "controls" for comparison. However, this is likely to contribute to type II error, since a particular biological finding may be applicable only to a subset of depressed patients. To illustrate this point, take a study from our own research laboratory ( Figure 1).(5) In this study, protein kinase A (PKA) activity was determined in fibroblasts in Mailing address: 1500 21st Avenue, South, Suite 2200, Nashville, TN 37212, Email: richard.shelton@vanderbilt.edu. Supported in part by NIMH grants MH073630, MH01741, and MH52339.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable fo...

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Expression of the neurotrophin receptor trkB is regulated by the cAMP/CREB pathway in neurons

Cited by 87 publications

References 41 publications

Ca2+, CREB and krüppel: A novel KLF7-binding element conserved in mouse and human TRKB promoters is required for CREB-dependent transcription

Ca2+, CREB and krüppel: A novel KLF7-binding element conserved in mouse and human TRKB promoters is required for CREB-dependent transcription

Modulation of the cAMP signaling pathway after traumatic brain injury

The Molecular Neurobiology of Depression

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