The Baker Laboratory of Pharmacology, Department of Pharmacology, Kirksville College of Osteopathic Medicine, A.T. Still University of Health Sciences, Kirksville, Missouri.
J Neurophysiol. 2022 Oct 1;128(4):739-750. doi: 10.1152/jn.00116.2022. Epub 2022 Aug 31.
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 (Na) 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 Na 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 Na1.9 channels as the target for this enhancement. When applied individually at the concentration used in the mixture, only prostaglandin and bradykinin significantly enhanced Na 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 Na1.9 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 Na1.9 channel activity is a likely mechanism by which GPCR activation increases action potential activity in afferents generating the EPR. 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 Na1.9 current is synergistically enhanced by application of a mixture of metabolites potentially released during muscle contraction. The enhancement of Na1.9 current is likely one mechanism by which GPCR activation generates the EPR and the inappropriate activation of the EPR in patients with cardiovascular disease.
骨骼肌收缩引发运动加压反射（EPR）以调节心血管系统对运动的反应。在肌肉收缩过程中，会释放出一些物质，这些物质在介导 EPR 的 III 类和 IV 类传入纤维中产生动作电位活动。其中一些物质通过 G 蛋白偶联受体（GPCR）激活增加传入纤维的活动，但机制尚不完全清楚。我们感兴趣的是确定河豚毒素抗性（TTX-R）电压门控钠通道（Na）是否参与其中，并研究了这种化合物混合物（缓激肽、前列腺素、去甲肾上腺素和 ATP，称为肌肉代谢物）的影响。使用全细胞膜片钳电生理学，我们表明肌肉代谢物显著增加了 TTX-R Na 电流。这种增强的上升时间平均约为 2 分钟，这表明涉及可扩散的第二信使途径。肌肉代谢物对电流-电压关系、通道激活和失活动力学的影响支持 Na1.9 通道作为这种增强的靶标。当以混合物中使用的浓度单独应用时，只有前列腺素和缓激肽显著增强了 Na 电流，但这些增强的总和小于当肌肉代谢物一起应用时观察到的增强的 1/3。这表明激活的 GPCR 之间存在协同作用，以增强 Na1.9 电流。当以更高的浓度应用时，所有四种物质都可以增强电流，这表明每种代谢物激活的 GPCR 可以增强通道活性。Na1.9 通道活性的增强可能是 GPCR 激活增加传入纤维中动作电位活动从而产生 EPR 的一种机制。G 蛋白偶联受体（GPCR）激活增加肌肉传入纤维的动作电位活动，产生运动加压反射（EPR），但其机制尚不完全清楚。我们提供的证据表明，应用肌肉收缩过程中潜在释放的代谢物混合物可协同增强 Na1.9 电流。Na1.9 电流的增强可能是 GPCR 激活产生 EPR 的一种机制，也是心血管疾病患者 EPR 异常激活的一种机制。
