Isoform Specificity of PKMs during Long-Term Facilitation in Aplysia Is Mediated through Stabilization by KIBRA
Isoform Specificity of PKMs during Long-Term Facilitation in Aplysia Is Mediated through Stabilization by KIBRA
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DOI：
10.1523/jneurosci.0943-19.2019
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发表时间：
2019-10-30
影响因子：
5.3
通讯作者：
Sossin, Wayne S.
中科院分区：
文献类型：
--
作者：
Ferguson, Larissa;Hu, Jiangyuan;Sossin, Wayne S.
蛋白激酶C （PKC）的截断形式蛋白激酶M （PKM）的持续活性可以维持许多系统中突触强度的长期变化，包括雌雄同体海洋软体动物加州海陆。此外，不同类型的长时程促进（LTF）依赖于突触前感觉神经元和突触后运动神经元中不同PKM亚型的活性。当需要非典型PKM异构体时，也需要肾和脑表达的适应蛋白（KIBRA）。在这里，我们探讨这种异构体特异性是如何建立的。我们发现PKM在运动神经元中的过度表达，而不是在感觉神经元中，足以增加突触强度，并且这种活动不是同型特异性的。KIBRA不是促进的限速步骤，因为KIBRA的过表达既不足以增加突触强度，也不足以延长pkm依赖的中间突触促进的形式。然而，显性阴性pkms清除LTF的同种异构体特异性与KIBRA稳定同种异构体特异性竞争相关。我们确定了一个新的KIBRA保守区域。该区域的不同剪接异构体根据pkm中a-螺旋“柄”的异构体特异性序列稳定不同的pkm。因此，KIBRA的不同异构体对不同PKMs的特异性稳定可以解释亚洲PKMs在LTF期间的异构体特异性。
Persistent activity of protein kinase M (PKM), the truncated form of protein kinase C (PKC), can maintain long-term changes in synaptic strength in many systems, including the hermaphrodite marine mollusk, Aplysia californica. Moreover, different types of long-term facilitation (LTF) in cultured Aplysia sensorimotor synapses rely on the activities of different PKM isoforms in the presynaptic sensory neuron and postsynaptic motor neuron. When the atypical PKM isoform is required, the kidney and brain expressed adaptor protein (KIBRA) is also required. Here, we explore how this isoform specificity is established. We find that PKM overexpression in the motor neuron, but not the sensory neuron, is sufficient to increase synaptic strength and that this activity is not isoform-specific. KIBRA is not the rate-limiting step in facilitation since overexpression of KIBRA is neither sufficient to increase synaptic strength, nor to prolong a form of PKM-dependent intermediate synaptic facilitation. However, the isoform specificity of dominant-negative-PKMs to erase LTF is correlated with isoform-specific competition for stabilization by KIBRA. We identify a new conserved region of KIBRA. Different splice isoforms in this region stabilize different PKMs based on the isoform-specific sequence of an a-helix "handle" in the PKMs. Thus, specific stabilization of distinct PKMs by different isoforms of KIBRA can explain the isoform specificity of PKMs during LTF in Aplysia.