MRC LMCB, University College, London, WC1E 6BT, United Kingdom.
Genetics. 2014 Mar;196(3):601-4. doi: 10.1534/genetics.113.159905.
Ca(2+)/calmodulin-dependent Kinase II (CaMKII) is a calcium-regulated serine threonine kinase whose functions include regulation of synaptic activity (Coultrap and Bayer 2012). A postsynaptic role for CaMKII in triggering long-lasting changes in synaptic activity at some synapses has been established, although the relevant downstream targets remain to be defined (Nicoll and Roche 2013). A presynaptic role for CaMKII in regulating synaptic activity is less clear with evidence for CaMKII either increasing or decreasing release of neurotransmitter from synaptic vesicles (SVs) (Wang 2008). In this issue Hoover et al. (2014) further expand upon the role of CaMKII in presynaptic cells by demonstrating a role in regulating another form of neuronal signaling, that of dense core vesicles (DCVs), whose contents can include neuropeptides and insulin-related peptides, as well as other neuromodulators such as serotonin and dopamine (Michael et al. 2006). Intriguingly, Hoover et al. (2014) demonstrate that active CaMKII is required cell autonomously to prevent premature release of DCVs after they bud from the Golgi in the soma and before they are trafficked to their release sites in the axon. This role of CaMKII requires it to have kinase activity as well as an activating calcium signal released from internal ER stores via the ryanodine receptor. Not only does this represent a novel function for CaMKII but also it offers new insights into how DCVs are regulated. Compared to SVs we know much less about how DCVs are trafficked, docked, and primed for release. This is despite the fact that neuropeptides are major regulators of human brain function, including mood, anxiety, and social interactions (Garrison et al. 2012; Kormos and Gaszner 2013; Walker and Mcglone 2013). This is supported by studies showing mutations in genes for DCV regulators or cargoes are associated with human mental disorders (Sadakata and Furuichi 2009; Alldredge 2010; Quinn 2013; Quinn et al. 2013). We lack even a basic understanding of DCV function, such as, are there defined DCV docking sites and, if so, how are DCVs delivered to these release sites? These results from Hoover et al. (2014) promise to be a starting point in answering some of these questions.
钙/钙调蛋白依赖性激酶 II（CaMKII）是一种钙调节丝氨酸/苏氨酸激酶，其功能包括调节突触活动（Coultrap 和 Bayer，2012）。CaMKII 在某些突触中触发突触活动的长时程变化的突触后作用已得到确立，尽管相关的下游靶标仍有待确定（Nicoll 和 Roche，2013）。CaMKII 在调节突触活动中的突触前作用不太清楚，有证据表明 CaMKII 既可以增加也可以减少突触小泡（SVs）释放神经递质（Wang，2008）。在本期杂志中，Hoover 等人（2014）通过证明 CaMKII 在调节另一种形式的神经元信号转导中的作用，进一步扩展了 CaMKII 在突触前细胞中的作用，这种信号转导是致密核心囊泡（DCVs）的信号转导，其内容可以包括神经肽和胰岛素相关肽，以及其他神经调质，如血清素和多巴胺（Michael 等人，2006）。有趣的是，Hoover 等人（2014）表明，活性 CaMKII 自主需要细胞来防止 DCVs 在从高尔基体出芽到轴突释放部位运输之前过早释放。CaMKII 的这种作用需要它具有激酶活性以及通过肌醇 1,4,5-三磷酸受体从内质网内部储存中释放的激活钙信号。这不仅代表了 CaMKII 的新功能，也为 DCVs 的调节提供了新的见解。与 SVs 相比，我们对 DCVs 的运输、 docking 和引发释放的了解要少得多。尽管神经肽是人类大脑功能的主要调节剂，包括情绪、焦虑和社交互动（Garrison 等人，2012；Kormos 和 Gaszner，2013；Walker 和 Mcglone，2013）。这一事实得到了研究的支持，这些研究表明，DCV 调节因子或货物的基因突变与人类精神障碍有关（Sadakata 和 Furuichi，2009；Alldredge，2010；Quinn，2013；Quinn 等人，2013）。我们甚至缺乏对 DCV 功能的基本了解，例如，是否存在定义明确的 DCV docking 位点，如果存在，DCVs 如何被递送到这些释放位点？Hoover 等人（2014）的这些结果有望成为回答其中一些问题的起点。
