Inhibition of neurotransmitter release by a nonphysiological target requires protein synthesis and involves cAMP-dependent and mitogen-activated protein kinases
Inhibition of neurotransmitter release by a nonphysiological target requires protein synthesis and involves cAMP-dependent and mitogen-activated protein kinases
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DOI：
10.1523/jneurosci.5671-03.2004
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发表时间：
2004-05-26
影响因子：
5.3
通讯作者：
Montarolo, PG
中科院分区：
文献类型：
--
作者：
Ghirardi, M;Benfenati, F;Montarolo, PG
在神经元回路的发育过程中，轴突生长锥在到达适当的突触后伙伴之前可以接触许多不适当的目标。尽管众所周知，与突触伙伴的接触会上调突触前神经元的分泌机制，但对于防止与不适当的靶细胞形成连接所涉及的信号传导机制知之甚少。在这里，我们表明，与非生理性突触后靶标的接触通过需要持续蛋白质合成的主动机制来抑制 Helix 血清素能神经元 C1 轴突末端的神经递质释放，并导致 cAMP 依赖性蛋白激酶 (PKA) 和丝裂原激活蛋白激酶 (MAPK) - 细胞外信号相关激酶 (Erk) 途径的抑制。 cAMP-PKA或MAPK-Erk抑制剂阻止了通过阻断蛋白质合成而逆转非生理靶标的抑制作用，而cAMP-PKA激活促进的神经递质释放的去抑制不受MAPK-Erk抑制剂影响。数据表明，非生理目标对神经递质释放的抑制作用是一个主动过程，需要蛋白质合成，并涉及 MAPK - Erk 和 cAMP - PKA 途径的下调，这些蛋白激酶与生理目标神经元接触后被激活。这些机制可以根据神经末梢发育过程中接触的目标的性质来调节生长神经末梢的神经递质释放能力，从而在预防不适当伴侣之间的突触形成方面发挥相关作用。
During the development of neuronal circuits, axonal growth cones can contact many inappropriate targets before they reach an appropriate postsynaptic partner. Although it is well known that the contact with synaptic partners upregulates the secretory machinery of the presynaptic neuron, little is known about the signaling mechanisms involved in preventing the formation of connections with inappropriate target cells. Here, we show that the contact with a nonphysiological postsynaptic target inhibits neurotransmitter release from axonal terminals of the Helix serotonergic neuron C1 by means of an active mechanism requiring ongoing protein synthesis and leading to the inhibition of cAMP-dependent protein kinase (PKA) and mitogen-activated protein kinase (MAPK) -extracellular signal-related kinase (Erk) pathways. The reversal of the inhibitory effect of the nonphysiological target by blockade of protein synthesis was prevented by cAMP - PKA or MAPK - Erk inhibitors, whereas disinhibition of neurotransmitter release promoted by cAMP - PKA activation was not affected by MAPK - Erk inhibitors. The data indicate that the inhibitory effect of the nonphysiological target on neurotransmitter release is an active process that requires protein synthesis and involves the downregulation of the MAPK - Erk and cAMP - PKA pathways, the same protein kinases that are activated after contact with a physiological target neuron. These mechanisms could play a relevant role in the prevention of synapse formation between inappropriate partners by modulating the neurotransmitter release capability of growing nerve terminals according to the nature of the targets contacted during their development.