REGULATORY SUBUNITS OF CAMP-DEPENDENT PROTEIN-KINASES ARE DEGRADED AFTER CONJUGATION TO UBIQUITIN - A MOLECULAR MECHANISM UNDERLYING LONG-TERM SYNAPTIC PLASTICITY
REGULATORY SUBUNITS OF CAMP-DEPENDENT PROTEIN-KINASES ARE DEGRADED AFTER CONJUGATION TO UBIQUITIN - A MOLECULAR MECHANISM UNDERLYING LONG-TERM SYNAPTIC PLASTICITY
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DOI：
10.1073/pnas.90.16.7436
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发表时间：
1993-08-15
影响因子：
11.1
通讯作者：
SCHWARTZ, JH
中科院分区：
文献类型：
--
作者：
HEGDE, AN;GOLDBERG, AL;SCHWARTZ, JH
在澳大利亚，防御性反射的行为敏化和潜在的感觉-运动神经元突触的突触前促进持续几分钟（短期）或数天至数周（长期）。短期致敏可以通过camp依赖性蛋白磷酸化调节离子通道功能来解释。长期促进需要额外的分子变化，包括蛋白质合成。一个关键事件是在cAMP基线浓度下cAMP依赖性蛋白激酶的持续激活。这种活化是由于PKA的调节(R)亚基选择性丧失，而催化(C)亚基没有任何变化。为了了解R亚基在长期易化过程中丢失的分子机制，我们研究了R亚基在海兔神经组织提取物和兔网织细胞裂解物中的降解情况。海藓R亚基的降解需要ATP、泛素和一种似乎是蛋白酶体复合物的颗粒成分。降解被血红蛋白阻断，导致高分子量R亚基衍生物的积累，这些衍生物可能是R亚基的泛素偶联物和降解途径中的中间体。我们还发现脊椎动物R(I)和R（II）亚基可以通过泛素途径降解。我们认为，降解是由cAMP启动的，它导致全酶解离，此外，新合成的蛋白质有助于目标R亚基加速降解，从而维持了海芋感觉神经元中R- c比率的改变。
In Aplysia, behavioral sensitization of defensive reflexes and the underlying presynaptic facilitation of sensory-to-motor neuron synapses lasts for several minutes (short term) or days to weeks (long term). Short-term sensitization has been explained by modulation of ion-channel function through cAMP-dependent protein phosphorylation. Long-term facilitation requires additional molecular changes including protein synthesis. A key event is the persistent activation of the cAMP-dependent protein kinase at baseline concentrations of cAMP. This activation is due to selective loss of regulatory (R) subunits of PKA without any change in catalytic (C) subunits. To understand the molecular mechanisms that produce the loss of R subunits in long-term facilitation, we investigated how R subunits are degraded in extracts of Aplysia nervous tissue and in rabbit reticulocyte lysates. Degradation of Aplysia R subunits requires ATP, ubiquitin, and a particulate component that appears to be the proteasome complex. Degradation is blocked by hemin, which causes the accumulation of high molecular weight derivatives of R subunits that are likely to be ubiquitin conjugates of R subunits and intermediates in the degradative pathway. We also show that vertebrate R(I) and R(II) subunits can be degraded through the ubiquitin pathway. We suggest that degradation is initiated by cAMP, which causes the holoenzyme to dissociate and, further, that the altered R-to-C ratio in Aplysia sensory neurons is maintained in long-term facilitation by newly synthesized proteins that help target R subunits for accelerated degradation.