Boillat Aurélien, Alijevic Omar, Kellenberger Stephan
Department of Pharmacology and Toxicology, University of Lausanne, 1005 Lausanne, Switzerland.
Department of Pharmacology and Toxicology, University of Lausanne, 1005 Lausanne, Switzerland.
Mol Cell Neurosci. 2014 Jul;61:13-22. doi: 10.1016/j.mcn.2014.04.007. Epub 2014 Apr 30.
Inflammatory mediators induce neuropeptide release from nociceptive nerve endings and cell bodies, causing increased local blood flow and vascular leakage resulting in edema. Neuropeptide release from sensory neurons depends on an increase in intracellular Ca(2+) concentration. In this study we investigated the role of two types of pH sensors in acid-induced Ca(2+) entry and neuropeptide release from dorsal root ganglion (DRG) neurons. The transient receptor potential vanilloid 1 channel (TRPV1) and acid-sensing ion channels (ASICs) are both H(+)-activated ion channels present in these neurons, and are therefore potential pH sensors for this process. We demonstrate with in situ hybridization and immunocytochemistry that TRPV1 and several ASIC subunits are co-expressed with neuropeptides in DRG neurons. The activation of ASICs and of TRPV1 led to an increase in intracellular Ca(2+) concentration. While TRPV1 has a high Ca(2+) permeability and allows direct Ca(2+) entry when activated, we show here that ASICs of DRG neurons mediate Ca(2+) entry mostly by depolarization-induced activation of voltage-gated Ca(2+) channels and only to a small extent via the pore of Ca(2+)-permeable ASICs. Extracellular acidification led to the release of the neuropeptide calcitonin gene-related peptide from DRG neurons. The pH dependence and the pharmacological profile indicated that TRPV1, but not ASICs, induced neuropeptide secretion. In conclusion, this study shows that although both TRPV1 and ASICs mediate Ca(2+) influx, TRPV1 is the principal sensor for acid-induced neuropeptide secretion from sensory neurons.
炎症介质可诱导伤害性神经末梢和细胞体释放神经肽，导致局部血流增加和血管渗漏，进而引起水肿。感觉神经元释放神经肽取决于细胞内钙离子（Ca(2+)）浓度的升高。在本研究中，我们调查了两种类型的pH传感器在酸诱导的Ca(2+)内流以及背根神经节（DRG）神经元神经肽释放中的作用。瞬时受体电位香草酸亚型1通道（TRPV1）和酸敏感离子通道（ASICs）都是存在于这些神经元中的H(+)激活离子通道，因此是该过程潜在的pH传感器。我们通过原位杂交和免疫细胞化学证明，TRPV1和几种ASIC亚基与神经肽在DRG神经元中共表达。ASICs和TRPV1的激活导致细胞内Ca(2+)浓度升高。虽然TRPV1具有高Ca(2+)通透性，激活时允许直接Ca(2+)内流，但我们在此表明，DRG神经元的ASICs介导Ca(2+)内流主要是通过去极化诱导电压门控Ca(2+)通道的激活，仅在小程度上通过Ca(2+)通透ASICs的孔道。细胞外酸化导致DRG神经元释放神经肽降钙素基因相关肽。pH依赖性和药理学特征表明，是TRPV1而非ASICs诱导神经肽分泌。总之，本研究表明，虽然TRPV1和ASICs都介导Ca(2+)内流，但TRPV1是感觉神经元酸诱导神经肽分泌的主要传感器。
