Activation of MEK/ERK signaling contributes to the PACAP-induced increase in guinea pig cardiac neuron excitability.
Activation of MEK/ERK signaling contributes to the PACAP-induced increase in guinea pig cardiac neuron excitability.
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DOI：
10.1152/ajpcell.00164.2016
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发表时间：
2016-08
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通讯作者：
J. Tompkins;Todd A. Clason;J. Hardwick;B. Girard;L. A. Merriam;V. May;R. Parsons
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文献类型：
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作者：
J. Tompkins;Todd A. Clason;J. Hardwick;B. Girard;L. A. Merriam;V. May;R. Parsons
腺苷酸环化酶（PAC）激活多肽（PACAP）肽（Adcyap 1）在选择性PAC 1受体（Adcyap 1 r1）上的信号传导参与多种稳态和应激相关反应，但PACAP作用的细胞机制仍有待完全阐明。PACAP/PAC 1受体信号传导增加豚鼠心脏神经节内神经元的兴奋性，并且由于这些神经元容易接近，因此该神经元系统特别适合于研究离子电导的PACAP调节。本研究探讨了PACAP如何激活MEK/ERK信号通路，促进肽诱导的心脏神经元兴奋性增加。用MEK抑制剂PD 98059治疗阻断了PACAP刺激的磷酸化ERK，并且平行地抑制了心脏神经元兴奋性的增加。然而，PD 98059并没有减弱PACAP增强两个内向离子电流的能力，一个流经超极化激活的非选择性阳离子通道（Ih），另一个流经低压激活的钙通道（IT），这支持了肽诱导的兴奋性增加。因此，除了Ih和IT之外，PACAP和MEK/ERK敏感的电压依赖性电导调节神经元兴奋性。尽管先前的工作暗示PACAP下调KV4.2钾通道在其他细胞的兴奋性的调制，与KV4.2电流阻断剂4-氨基吡啶治疗没有复制PACAP诱导的心脏神经元的兴奋性增加。然而，心脏神经元表达ERK靶点，NaV1.7钠通道，用选择性NaV1.7通道抑制剂PF-04856264处理降低了兴奋性的PACAP调节。根据这些结果，PACAP/PAC 1激活MEK/ERK信号可能磷酸化NaV1.7通道，增强阈值附近的钠电流，这一作用有助于暴露于PACAP的心脏神经元的重复放电。
Pituitary adenylate cyclase (PAC)-activating polypeptide (PACAP) peptides (Adcyap1) signaling at the selective PAC1 receptor (Adcyap1r1) participate in multiple homeostatic and stress-related responses, yet the cellular mechanisms underlying PACAP actions remain to be completely elucidated. PACAP/PAC1 receptor signaling increases excitability of neurons within the guinea pig cardiac ganglia, and as these neurons are readily accessible, this neuronal system is particularly amenable to study of PACAP modulation of ionic conductances. The present study investigated how PACAP activation of MEK/ERK signaling contributed to the peptide-induced increase in cardiac neuron excitability. Treatment with the MEK inhibitor PD 98059 blocked PACAP-stimulated phosphorylated ERK and, in parallel, suppressed the increase in cardiac neuron excitability. However, PD 98059 did not blunt the ability of PACAP to enhance two inward ionic currents, one flowing through hyperpolarization-activated nonselective cationic channels (Ih) and another flowing through low-voltage-activated calcium channels (IT), which support the peptide-induced increase in excitability. Thus a PACAP- and MEK/ERK-sensitive, voltage-dependent conductance(s), in addition to Ih and IT, modulates neuronal excitability. Despite prior work implicating PACAP downregulation of the KV4.2 potassium channel in modulation of excitability in other cells, treatment with the KV4.2 current blocker 4-aminopyridine did not replicate the PACAP-induced increase in excitability in cardiac neurons. However, cardiac neurons express the ERK target, the NaV1.7 sodium channel, and treatment with the selective NaV1.7 channel inhibitor PF-04856264 decreased the PACAP modulation of excitability. From these results, PACAP/PAC1 activation of MEK/ERK signaling may phosphorylate the NaV1.7 channel, enhancing sodium currents near the threshold, an action contributing to repetitive firing of the cardiac neurons exposed to PACAP.