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【正文】 → PKA activation↓ ? cAMP unfixed → PKAactivation↑ → PP1 activity↓ ? Active PP1 →dephosphorylate CaMKII(Thr286) →CaMKII ↓. 2.(2) (E) CaN (PP2B) activation by Ca/CaM elevation. ? The full model–cAMP fixed curves overlap almost erfectly. ? ↓ ? CaN uninfluenced by cAMP 四、 3. A model for interaction between 4 signaling pathways: form a work ( PKC、 MAPK pathways + CaMKII、 cAMP pathways ) Glu(+postsynaptic depolarization) →Ca2+ influx through NMDAR→ [Ca2+]↑ →postsynaptic PK(CaMKII,PKC,PKA,MAPK) ↑ 四、 3. Combined model with feedback loop, synaptic input, and CaMKII activity and Regulation. cPLA2(held activity) →less AA→ FBOFF MKP(timer of FB in early LTP of synapse)→FBOFF cPLA2(activity↑) → AA↑→ FBON 四、 3. Activity profile of major enzymes in pathway ?Fig B to G ▲ ： full model(FBON) □ ： feedback blocked(FBOFF) (AA fixed at resting concentrations) ?FBON : present feedback ?FBOFF : absence feedback 四、 3. (B) Activity profile of PKC ? FBOFF : →PKC↓ ? FBON →larger successive spikes ? (initial spike+FBON ) →DAG+AA→PKC↑↑ 四、 3. (C) Activity profile of MAPK ? FBON →MAPK turn on ? FBOFF →MAPK turn off ? (initial spike+FBON ) →DAG+AA ? →PKC↑↑→MAPK↑(steady) ? 四、 3. (D) Activity profile of PKA. ? Ca2+ inflow→AC1,8↑→PKA↑ Ca2+ → identical PKA ↑ ? FBON : PKC→ AC2↑→ cAMP↑→PKA ↑↑ ? sustained PKC→sustained ? PKA activity Several emergent properties of work ? (1).Extended signal duration. ? (2).Activation of feedback loop. ? (3).Definition of threshold stimulation for ? biological effects. ? (4).Multiple signal outputs. 四、 3. (E) Activity profile of CaMKII. ? Ca2+ inflow→CaMKII↑ ? Ca2+ → identical CaMKII ↑ ? FBON : PKC→ AC2↑→ cAMP↑→PKA baseline ↑(twofold) ? PKA↑→PP1↓→CaMKII↑ ? { [dephosphorylate CaMKII(Thr286)] →CaMKII autophosphorylation↓} 四、 3. (F) Activity profile of PP1. ? Ca2+→PP1↓ ? (overlap:FBON,FBOFF) ? FBON→PKA↑(sustained)→PP1↓→ PP1 (sustained) ? CaMKII↑ 四、 (G) Activity profile of CaN (PP2B). ? FBOFF or FBON： ? CaN is naffected ? →its’ effect on PP1 limited to the duration of the initial signals. On Network ? (1).Network→sustained PK activity(after initial stimulus) ? correspond to early LTP ? (2). MKP induction→ Other transcriptional events be initiated → ? gene products→reach the active synapse with MKP ? (3).FBloop may gate incorporation of these products into the cytoskeleton. ? act as bridge between extremly short stimuli and longer term synaptic change and also between local synaptic events and cell wide production of synaptic proteins. On the model ? (1).Such a model facilitates “thought experiments” on ? involved signaling pathways to predict hierarchies. ? (2). The model also provides a framework for understanding ? biological consequences of multiple modes of ? stimulating a single ponent. ? (3).Such models provide insights into the possible roles of ? isoform diversity. ? [CaM→AC1,PKC→AC2(connection,sustain CaMKII activation)] On the model ? (4).Limitations: ? The biochemical parameters are not unaltered with the cell. Given these uncertainties, models such as these should not be considered as definitive descriptions of works within the cell, but rather as one approach that allows us to understand the capabilities of plex systems and devise experiments to test these capabilities. ? (5). Conclusion: ? simple biochemical reactions can, with appropriate coupling, be used to store information. Thus, reactions within signaling pathways may constitute one locus for the biochemical basis for learning and memory.
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