The palmitoyl acyltransferase ZDHHC14 controls Kv1-family potassium channel clustering at the axon initial segment.
The palmitoyl acyltransferase ZDHHC14 controls Kv1-family potassium channel clustering at the axon initial segment.
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DOI：
10.7554/elife.56058
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发表时间：
2020-11-13
期刊：
影响因子：
7.7
通讯作者：
Thomas GM
中科院分区：
文献类型：
--
作者：
Sanders SS;Hernandez LM;Soh H;Karnam S;Walikonis RS;Tzingounis AV;Thomas GM
棕榈酰酰基转移酶（PAT）ZDHHC14在海马体中高度表达，并且是预测结合含I型PDZ结构域的蛋白质的唯一PAT。然而，ZDHHC14的神经元作用是未知的。在这里，我们确定PDZ结构域包含膜相关鸟苷酸激酶（MaGUK）PSD93作为直接ZDHHC14相互作用和底物。PSD 93而不是其他MaGUK定位于轴突起始段（AIS）。在大鼠海马神经元中使用慢病毒介导的shRNA敲低，我们发现ZDHHC14控制PSD93和Kv1钾通道的棕榈酰化和AIS聚类，Kv1钾通道直接结合PSD93。ZDHHC14的神经发育表达反映了PSD93和Kv1通道的表达，并且与ZDHHC14对Kv1通道聚集的重要性一致，ZDHHC14的缺失降低了外向电流并增加了海马神经元中的动作电位放电。据我们所知，这些发现确定了ZDHHC14的第一个神经元作用和底物，并揭示了棕榈酰化在控制神经元兴奋性中的先前未被认识的作用。
The palmitoyl acyltransferase (PAT) ZDHHC14 is highly expressed in the hippocampus and is the only PAT predicted to bind Type-I PDZ domain-containing proteins. However, ZDHHC14’s neuronal roles are unknown. Here, we identify the PDZ domain-containing Membrane-associated Guanylate Kinase (MaGUK) PSD93 as a direct ZDHHC14 interactor and substrate. PSD93, but not other MaGUKs, localizes to the axon initial segment (AIS). Using lentiviral-mediated shRNA knockdown in rat hippocampal neurons, we find that ZDHHC14 controls palmitoylation and AIS clustering of PSD93 and also of Kv1 potassium channels, which directly bind PSD93. Neurodevelopmental expression of ZDHHC14 mirrors that of PSD93 and Kv1 channels and, consistent with ZDHHC14’s importance for Kv1 channel clustering, loss of ZDHHC14 decreases outward currents and increases action potential firing in hippocampal neurons. To our knowledge, these findings identify the first neuronal roles and substrates for ZDHHC14 and reveal a previously unappreciated role for palmitoylation in control of neuronal excitability.