PDF(Pubmed)
Abstract：
Skeletal muscle contraction triggers the exercise pressor reflex (EPR) to regulate the cardiovascular system response to exercise. During muscle contraction, substances are released that generate action potential activity in group III and IV afferents that mediate the EPR. Some of these substances increase afferent activity via G-protein-coupled receptor (GPCR) activation, but the mechanisms are incompletely understood. We were interested in determining if tetrodotoxin-resistant (TTX-R) voltage-dependent sodium channels (NaV) were involved and investigated the effect of a mixture of such compounds (bradykinin, prostaglandin, norepinephrine, and ATP, called muscle metabolites). Using whole cell patch-clamp electrophysiology, we show that the muscle metabolites significantly increased TTX-R NaV currents. The rise time of this enhancement averaged ∼2 min, which suggests the involvement of a diffusible second messenger pathway. The effect of muscle metabolites on the current-voltage relationship, channel activation and inactivation kinetics support NaV1.9 channels as the target for this enhancement. When applied individually at the concentration used in the mixture, only prostaglandin and bradykinin significantly enhanced NaV current, but the sum of these enhancements was <1/3 that observed when the muscle metabolites were applied together. This suggests synergism between the activated GPCRs to enhance NaV1.9 current. When applied at a higher concentration, all four substances could enhance the current, which demonstrates that the GPCRs activated by each metabolite can enhance channel activity. The enhancement of NaV1.9 channel activity is a likely mechanism by which GPCR activation increases action potential activity in afferents generating the EPR.NEW & NOTEWORTHY G-protein-coupled receptor (GPCR) activation increases action potential activity in muscle afferents to produce the exercise pressor reflex (EPR), but the mechanisms are incompletely understood. We provide evidence that NaV1.9 current is synergistically enhanced by application of a mixture of metabolites potentially released during muscle contraction. The enhancement of NaV1.9 current is likely one mechanism by which GPCR activation generates the EPR and the inappropriate activation of the EPR in patients with cardiovascular disease.
摘要：
骨骼肌收缩会触发运动压力反射（EPR），以调节心血管系统对运动的反应。肌肉收缩时,释放的物质在介导EPR的III和IV组传入中产生动作电位活性。这些物质中的一些通过G蛋白偶联受体（GPCR）激活增加传入活性，但是机制还不完全清楚。我们有兴趣确定是否涉及抗河豚毒素（TTX-R）电压依赖性钠通道（NaV），并研究了此类化合物混合物（缓激肽，前列腺素,去甲肾上腺素,ATP,称为肌肉代谢物)。使用全细胞膜片钳电生理学，我们表明，肌肉代谢物显着增加TTX-RNaV电流。这种增强的上升时间平均为2分钟，这表明参与了可扩散的第二信使途径。肌肉代谢物对电流-电压关系的影响，通道激活和失活动力学支持NaV1.9通道作为这种增强的目标。以混合物中使用的浓度单独施用时，只有前列腺素和缓激肽显着增强NaV电流，但是当肌肉代谢物一起应用时，这些增强的总和<1/3。这表明活化的GPCR之间的协同作用以增强NaV1.9电流。当在较高浓度下使用时，所有四种物质都可以增强电流，这表明由每种代谢物激活的GPCRs可以增强通道活性。NaV1.9通道活性的增强是GPCR激活增加产生EPR的传入体中的动作电位活性的可能机制。NEW和NOTEWORTHYG蛋白偶联受体（GPCR）激活增加了肌肉传入的动作电位活性，从而产生运动压迫反射（EPR），但是机制还不完全清楚。我们提供证据表明，通过应用在肌肉收缩过程中可能释放的代谢物混合物，NaV1.9电流可协同增强。NaV1.9电流的增强可能是心血管疾病患者中GPCR激活产生EPR和EPR不适当激活的一种机制。
