Enhanced cAMP Response Element-Binding Protein Activity Increases Neuronal Excitability, Hippocampal Long-Term Potentiation, and Classical Eyeblink Conditioning in Alert Behaving Mice

The distribution of transducers of regulated cAMP-response element-binding protein activity (TORC) between the cytoplasm and the nucleus is tightly regulated and represents one of the main mechanisms whereby the cAMP response element activation activities of TORC are controlled. Whereas both cAMP and Ca2+ pathways can cause translocation of TORC, the relative importance of these two pathways in regulating different TORC within the same cell is unclear. In this study, we determined the mechanism that regulated TORC1 translocation and compared it with that of TORC2 in rat pinealocytes. Stimulation of pinealocytes with norepinephrine (NE), although having no effect on Torc1 transcription, caused rapid dephosphorylation of TORC1. Although NE also caused rapid dephosphorylation of TORC2, pharmacological studies revealed that TORC1 dephosphorylation could be induced by both β-adrenoceptor/cAMP and α-adrenoceptor/intracellular Ca2+ pathways contrasting with TORC2 dephosphorylation being induced mainly through the β-adrenoceptor/cAMP pathway. PhosTag gel indicated a different pattern of TORC1 desphosphorylation resulting from the selective activation of α- or β-adrenoceptors. Interestingly, only the α-adrenoceptor/intracellular Ca2+-mediated dephosphorylation could translocate TORC1 to the nucleus, whereas the β-adrenoceptor/cAMP-mediated dephosphorylation of TORC1 was ineffective. In comparison, translocation of TORC2 was induced predominantly by the β-adrenoceptor/cAMP pathway. Studies with different protein phosphatase (PP) inhibitors indicated that the NE-mediated translocation of TORC1 was blocked by cyclosporine A, a PP2B inhibitor, but that of TORC2 was blocked by okadaic acid, a PP2A inhibitor. Together these results highlight different intracellular signaling pathways that are involved in the NE-stimulated dephosphorylation and translocation of TORC1 and TORC2 in rat pinealocytes.

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Long-Term Potentiation of Exocytosis and Cell Membrane Repair in Fibroblasts

Molecular Biology of the Cell ◽

10.1091/mbc.e02-01-0056 ◽

2003 ◽

Vol 14 (1) ◽

pp. 93-106 ◽

Cited By ~ 35

Author(s):

Tatsuru Togo ◽

Janet M. Alderton ◽

Richard A. Steinhardt

Keyword(s):

Long Term Potentiation ◽

Camp Response Element Binding ◽

Membrane Repair ◽

Regulated Exocytosis ◽

3T3 Fibroblasts ◽

Term Potentiation ◽

Element Binding Protein ◽

Dependent Protein ◽

Membrane Resealing

We previously found that a microdisruption of the plasma membrane evokes Ca2+-regulated exocytosis near the wound site, which is essential for membrane resealing. We demonstrate herein that repeated membrane disruption reveals long-term potentiation of Ca2+-regulated exocytosis in 3T3 fibroblasts, which is closely correlated with faster membrane resealing rates. This potentiation of exocytosis is cAMP-dependent protein kinase A dependent in the early stages (minutes), in the intermediate term (hours) requires protein synthesis, and for long term (24 h) depends on the activation of cAMP response element-binding protein (CREB). We were able to demonstrate that wounding cells activated CREB within 3.5 h. In all three phases, the increase in the amount of exocytosis was correlated with an increase in the rate of membrane resealing. However, a brief treatment with forskolin, which is effective for short-term potentiation and which could also activate CREB, was not sufficient to induce long-term potentiation of resealing. These results imply that long-term potentiation by CREB required activation by another, cAMP-independent pathway.

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CREB: A Multifaceted Target for Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205018666210218152253 ◽

2021 ◽

Vol 18 ◽

Author(s):

Vivek Kumar Sharma ◽

Thakur Gurjeet Singh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Binding Protein ◽

Camp Response Element Binding ◽

Camp Signaling ◽

Camp Response Element ◽

Response Element ◽

Term Memory ◽

Element Binding Protein

: Alzheimer’s disease (AD) is a persistent neuropathological stipulation manifested in the form of neuronal/synapse demise, the formation of senile plaques, hyperphosphorylated tau tangles, neuroinflammation, and apoptotic cell death. The absence of a therapeutic breakthrough for AD has continued the quest to find a suitable intervention. Apart from various candidates, the cyclic AMP-protein kinase A-cAMP response element-binding protein (cAMP/PKA/CREB) pathway is the most sought-after drug target AD as the bulk of quality literature documents that there is downregulation of cAMP signaling and CREB mediated transcriptional cascade in AD. cAMP signaling is evolutionarily conserved and can be found in all species. cAMP response element-binding protein (CREB) is a ubiquitous and integrally articulated transcription aspect that regulates neuronal growth, neuronal differentiation/proliferation, synaptic plasticity, neurogenesis, maturation of neurons, spatial memory, long-term memory formation as well as ensures neuronal survival. CREB is a central part of the molecular machinery that has a role in transforming short-term memory to long-term. Besides AD, impairment of CREB signaling has been well documented in addiction, Parkinsonism, schizophrenia, Huntington’s disease, hypoxia, preconditioning effects, ischemia, alcoholism, anxiety, and depression. The current work highlights the role and influence of CREB mediated transcriptional signaling on major pathological markers of AD (amyloid β, neuronal loss, inflammation, apoptosis, etc.). The present work justifies the continuous efforts being made to explore the multidimensional role of CREB and related downstream signaling pathways in cognitive deficits and neurodegenerative complications in general and AD particularly. Moreover, it is reaffirmed that cyclic nucleotide signaling may have vast potential to treat neurodegenerative complications like AD.

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