Neurotransmitter Switching Coupled to β-Adrenergic Signaling in Sympathetic Neurons in Prehypertensive States.
Neurotransmitter Switching Coupled to β-Adrenergic Signaling in Sympathetic Neurons in Prehypertensive States.
复制标题
DOI：
10.1161/hypertensionaha.118.10844
复制
发表时间：
2018-06
期刊：
影响因子：
--
通讯作者：
Paterson DJ
中科院分区：
文献类型：
--
作者：
Bardsley EN;Davis H;Buckler KJ;Paterson DJ
补充数字内容可在文本中找到。β受体阻滞剂的单一或组合施用是交感神经过度活跃引起的病症的主要治疗策略。传统观点认为，β受体阻滞剂的主要有益作用包括心肌中β1-肾上腺素能信号通路的再敏感化和恢复、心肌细胞收缩性的改善和心室敏化的逆转。然而，新出现的证据表明，β受体阻滞剂在疾病中的另一个有益作用可能存在于交感神经元中。我们研究了β-肾上腺素受体是否存在于节后交感神经元上，并以前馈方式促进神经传递。结合免疫细胞化学、RNA测序、Förster共振能量转移和细胞内Ca 2+成像，我们证明了人和大鼠星状神经节突触前交感神经元上存在β-肾上腺素能受体。在高血压前期大鼠的病变神经元中，主要通过β2-肾上腺素受体激活增强β-肾上腺素受体介导的信号传导。此外，在人类和大鼠神经元中，我们发现了肾上腺素合成酶PNMT（苯乙醇胺-N-甲基转移酶）的存在。使用高压液相色谱电化学检测，我们测量了更大的肾上腺素含量和诱发释放从高血压大鼠心脏星状神经节。我们的结论是，神经递质转换导致肾上腺素释放增强，可能提供突触前正反馈β-肾上腺素受体，以促进进一步释放，导致更大的突触后兴奋性疾病，动脉血压升高之前。靶向神经元β-肾上腺素受体下游信号传导可以提供治疗机会，以最大限度地减少交感神经过度活动引起的终末器官损伤。
Supplemental Digital Content is available in the text. Single or combinatorial administration of β-blockers is a mainstay treatment strategy for conditions caused by sympathetic overactivity. Conventional wisdom suggests that the main beneficial effect of β-blockers includes resensitization and restoration of β1-adrenergic signaling pathways in the myocardium, improvements in cardiomyocyte contractility, and reversal of ventricular sensitization. However, emerging evidence indicates that another beneficial effect of β-blockers in disease may reside in sympathetic neurons. We investigated whether β-adrenoceptors are present on postganglionic sympathetic neurons and facilitate neurotransmission in a feed-forward manner. Using a combination of immunocytochemistry, RNA sequencing, Förster resonance energy transfer, and intracellular Ca2+ imaging, we demonstrate the presence of β-adrenoceptors on presynaptic sympathetic neurons in both human and rat stellate ganglia. In diseased neurons from the prehypertensive rat, there was enhanced β-adrenoceptor–mediated signaling predominantly via β2-adrenoceptor activation. Moreover, in human and rat neurons, we identified the presence of the epinephrine-synthesizing enzyme PNMT (phenylethanolamine-N-methyltransferase). Using high-pressure liquid chromatography with electrochemical detection, we measured greater epinephrine content and evoked release from the prehypertensive rat cardiac-stellate ganglia. We conclude that neurotransmitter switching resulting in enhanced epinephrine release, may provide presynaptic positive feedback on β-adrenoceptors to promote further release, that leads to greater postsynaptic excitability in disease, before increases in arterial blood pressure. Targeting neuronal β-adrenoceptor downstream signaling could provide therapeutic opportunity to minimize end-organ damage caused by sympathetic overactivity.
影响因子：
4
作者：
Berg T
通讯作者：
Berg T