Multiple Mechanisms Contribute to the PAC1 Modulation of Parasympathetic Cardiac Neuron Excitability
Multiple Mechanisms Contribute to the PAC1 Modulation of Parasympathetic Cardiac Neuron Excitability
复制标题
多种机制有助于 PAC1 调节副交感心脏神经元兴奋性
DOI：
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
V. May
中科院分区：
文献类型：
--
作者：
R. Parsons;J. Tompkins;J. Hardwick;L. A. Merriam;B. Girard;V. May
腺苷酸环化酶激活多肽（PACAP）是一种有效的细胞间信号分子，其调节多种对行为和生理稳态重要的中枢和外周神经元回路。虽然中枢神经元不容易获得的机制研究，PACAP/PAC 1受体信号传导的能力，以增加豚鼠心副交感神经节神经元兴奋性提供了一个独特的手段，建立细胞内PACAP机制的神经元功能。豚鼠心脏神经元主要表达非常短的无效PAC 1受体亚型，其与腺苷酸环化酶和MEK/ERK信号级联反应偶联。腺苷酸环化酶的PACAP/PAC 1受体激活和由此产生的细胞内cAMP升高增强了非选择性阳离子电流Ih;用Ih抑制剂治疗减少了PACAP诱导的兴奋性增加。因此，Ih激活的电压依赖性的转变是PACAP诱导的心脏神经元兴奋性增加的一种离子机制。低浓度的镍也钝化肽诱导的兴奋性增加，表明PACAP增强的钙内流通过T型电压依赖性钙通道有助于兴奋性的调制。降低环境温度和用内吞抑制剂Pitstop 2或dynasore处理有效地阻断PACAP对兴奋性的调节，表明PACAP/PAC 1受体内化用于内体MEK/ERK活化是PACAP反应所必需的。总之，本综述中的结果表明，PACAP/PAC 1受体相互作用可以激活多个细胞内信号级联，选择性地调节离子电导门神经元兴奋性。
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a potent intercellular signaling molecule that regulates a variety of central and peripheral neuronal circuits important for behavior and physiological homeostasis. Although central neurons are not readily accessible for mechanistic studies, the ability for PACAP/PAC1 receptor signaling to increase neuronal excitability in guinea pig parasympathetic cardiac ganglia provides a unique means to establish intracellular PACAP mechanisms in neuronal function. The guinea pig cardiac neurons predominantly express a very short null PAC1 receptor isoform which is coupled to the adenylyl cyclase and MEK/ERK signaling cascades. PACAP/PAC1 receptor activation of adenylyl cyclase and the resulting rise in intracellular cAMP enhances the nonselective cationic current Ih; treatment with Ih inhibitors diminishes the PACAP-induced increase in excitability. Thus, a shift in the voltage-dependence of Ih activation is one ionic mechanism contributing to the PACAP-induced increase in cardiac neuron excitability. Low concentrations of nickel also blunt the peptide-induced increase in excitability, suggesting that a PACAP enhanced calcium influx through T-type voltage-dependent calcium channels contributes to the modulation of excitability. Reducing ambient temperature and treatments with endocytosis inhibitors Pitstop2 or dynasore efficaciously block PACAP modulation of excitability suggesting PACAP/PAC1 receptor internalization for endosomal MEK/ERK activation is requisite for the PACAP responses. In sum, the results presented in this review demonstrate that the PACAP/PAC1 receptor interactions can activate multiple intracellular signaling cascades to selectively modulate ionic conductances that gate neuronal excitability.
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影响因子：
5.5
作者：
May, Victor;Buttolph, Thomas R.;Parsons, Rodney L.
通讯作者：
Parsons, Rodney L.
影响因子：
3.4
作者：
Lee, JH;Gomora, JC;Perez-Reyes, E
通讯作者：
Perez-Reyes, E
成年大鼠心内神经元的钾电流。
DOI：
10.1113/jphysiol.1995.sp020787
发表时间：
1995
期刊：
The Journal of physiology
影响因子：
--
作者：
Xi-Moy,SX;Dun,NJ
通讯作者：
Dun,NJ
PACAP 在雄性小鼠应激转导的高内脏神经放电率特征下控制肾上腺髓质儿茶酚胺分泌和儿茶酚胺生物合成酶的表达。
影响因子：
4.8
作者：
Stroth,N;Kuri,BA;Mustafa,T;Chan,S-A;Smith,CB;Eiden,LE
通讯作者：
Eiden,LE