Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1.
Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1.
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DOI：
10.1111/j.1471-4159.2011.07330.x
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发表时间：
2011-08
影响因子：
4.7
通讯作者：
Hardingham GE
中科院分区：
文献类型：
--
作者：
Baxter PS;Martel MA;McMahon A;Kind PC;Hardingham GE
垂体腺苷酸环化酶激活肽（PACAP）是一种神经保护肽，主要通过cAMP-蛋白激酶A（PKA）途径发挥作用。在这里，我们发现，在皮质神经元中，PACAP 诱导的 PKA 信号传导通过触发动作电位 (AP) 放电，间接发挥其神经保护作用的主要部分。用 PACAP 治疗皮质神经元可诱导 AP 放电和相关细胞内 Ca2+ 瞬变的快速、持续的 PKA 依赖性增加，这对于 PACAP 的抗凋亡作用至关重要。短暂暴露于 PACAP 会在面对细胞凋亡损伤时诱导持久的神经保护，这依赖于 AP 放电和 cAMP 反应元件 (CRE) 结合蛋白 (CREB) 介导的基因表达的激活。尽管直接的、与活性无关的 PKA 信号传导足以触发 CREB 激活丝氨酸 133 位点的磷酸化，但这不足以激活 CREB 介导的基因表达。完全激活依赖于 CREB 调节的转录共激活因子 1 (CRTC1)，其 PACAP 诱导的核输入依赖于放电活性依赖性钙调神经磷酸酶信号传导。 CRTC1 的过表达足以在活性阻断时挽救 PACAP 诱导的 CRE 介导的基因表达，而显性失活 CRTC1 会干扰 PACAP 诱导的 CREB 介导的神经保护。因此，AP 放电的增强可能在 PACAP 和其他腺苷酸环化酶偶联配体的神经保护作用中发挥重要作用。
Pituitary adenylate cyclase-activating peptide (PACAP) is a neuroprotective peptide which exerts its effects mainly through the cAMP-protein kinase A (PKA) pathway. Here, we show that in cortical neurons, PACAP-induced PKA signaling exerts a major part of its neuroprotective effects indirectly, by triggering action potential (AP) firing. Treatment of cortical neurons with PACAP induces a rapid and sustained PKA-dependent increase in AP firing and associated intracellular Ca2+ transients, which are essential for the anti-apoptotic actions of PACAP. Transient exposure to PACAP induces long-lasting neuroprotection in the face of apoptotic insults which is reliant on AP firing and the activation of cAMP response element (CRE) binding protein (CREB)-mediated gene expression. Although direct, activity-independent PKA signaling is sufficient to trigger phosphorylation on CREB’s activating serine-133 site, this is insufficient for activation of CREB-mediated gene expression. Full activation is dependent on CREB-regulated transcription co-activator 1 (CRTC1), whose PACAP-induced nuclear import is dependent on firing activity-dependent calcineurin signaling. Over-expression of CRTC1 is sufficient to rescue PACAP-induced CRE-mediated gene expression in the face of activity-blockade, while dominant negative CRTC1 interferes with PACAP-induced, CREB-mediated neuroprotection. Thus, the enhancement of AP firing may play a significant role in the neuroprotective actions of PACAP and other adenylate cyclase-coupled ligands.
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DOI：
10.1111/j.1749-6632.2010.05512.x
发表时间：
2010-01-01
期刊：
PHYLOGENETIC ASPECTS OF NEUROPEPTIDES: FROM INVERTEBRATES TO HUMANS
影响因子：
--
作者：
Atlasz, T.;Szabadfi, K.;Reglodi, D.
通讯作者：
Reglodi, D.
影响因子：
3.9
作者：
Hardingham GE
通讯作者：
Hardingham GE
影响因子：
3.1
作者：
Dejda, Agnieszka;Jolivel, Valerie;Vaudry, David
通讯作者：
Vaudry, David
影响因子：
9.2
作者：
Bittinger, MA;McWhinnie, E;Labow, M
通讯作者：
Labow, M
影响因子：
56.9
作者：
Chawla, S;Hardingham, GE;Bading, H
通讯作者：
Bading, H