title: Notch-inducible hyperphosphorylated CREB and its ultradian oscillation in long-term memory formation.
abstract: Notch is a cell surface receptor that is known to regulate developmental processes by establishing physical contact between neighboring cells. Many recent studies show that it also plays an important role in the formation of long-term memory (LTM) in adults, implying that memory formation requires regulation at the level of cell-cell contacts among brain cells. Neither the target of Notch activity in LTM formation nor the underlying mechanism of regulation is known. We report here results of our studies in adult Drosophila melanogaster showing that Notch regulates dCrebB-17A, the CREB protein. CREB is a transcriptional factor that is pivotal for intrinsic and synaptic plasticity involved in LTM formation. Notch in conjunction with PKC activity upregulates the level of a hyperphosphorylated form of CREB (hyper-PO4 CREB) and triggers its ultradian oscillation, both of which are linked to LTM formation. One of the sites that is phosphorylated in hyper-PO4 CREB is serine 231, which is the functional equivalent of mammalian CREB serine 133, the phosphorylation of which is an important regulator of CREB functions. Our data suggest the model that Notch and PKC activities generate a cyclical accumulation of cytoplasmic hyper-PO4 CREB that is a precursor for generating the nuclear CREB isoforms. Cyclical accumulation of CREB might be important for repetitive aspects of LTM formation, such as memory consolidation. Because Notch, PKC, and CREB have been implicated in many neurodegenerative diseases (e.g., Alzheimer's disease), our data might also shed some light on memory loss and dementia.
authors.affiliation: Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Zhang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Little
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Tremmel
authors.forename: Jerry C P
authors.initials: JC
authors.lastname: Yin
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Wesley
mesh_terms: D000204:Activity Cycles / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000235:genetics; D003214:Conditioning, Classical / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D008297:Male; D057567:Memory, Long-Term / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D013696:Temperature; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; C497759:N protein, Drosophila; D010703:Phorbol Esters; D020033:Protein Isoforms; D051880:Receptors, Notch; C008874:phorbol-12,13-diacetate; D050882:CREB-Binding Protein; D011493:Protein Kinase C
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