Bahia Parmvir K, Taylor-Clark Thomas E
Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL, 33612, USA.
BMC Res Notes. 2021 Apr 7;14(1):127. doi: 10.1186/s13104-021-05539-2.
Transient receptor potential ankyrin 1 (TRPA1) is an excitatory ion channel expressed on a subset of sensory neurons. TRPA1 is activated by a host of noxious stimuli including pollutants, irritants, oxidative stress and inflammation, and is thought to play an important role in nociception and pain perception. TRPA1 is therefore a therapeutic target for diseases with nociceptive sensory signaling components. TRPA1 orthologs have been shown to have differential sensitivity to certain ligands. Cinnamaldehyde has previously been shown to activate sensory neurons via the selective gating of TRPA1. Here, we tested the sensitivity of cinnamaldehyde-evoked responses in mouse and guinea pig sensory neurons to the pore blocker ruthenium red (RuR).
Cinnamaldehyde, the canonical TRPA1-selective agonist, caused robust calcium fluxes in trigeminal neurons dissociated from both mice and guinea pigs. RuR effectively inhibited cinnamaldehyde-evoked responses in mouse neurons at 30 nM, with complete block seen with 3 μM. In contrast, responses in guinea pig neurons were only partially inhibited by 3 μM RuR. We conclude that RuR has a decreased affinity for guinea pig TRPA1 compared to mouse TRPA1. This study provides further evidence of differences in ligand affinity for TRPA1 in animal models relevant for drug development.
瞬时受体电位锚蛋白1（TRPA1）是一种在部分感觉神经元上表达的兴奋性离子通道。TRPA1可被多种有害刺激激活，包括污染物、刺激物、氧化应激和炎症，被认为在伤害感受和疼痛感知中起重要作用。因此，TRPA1是具有伤害性感觉信号成分疾病的治疗靶点。已证明TRPA1直系同源物对某些配体具有不同的敏感性。肉桂醛先前已被证明可通过TRPA1的选择性门控激活感觉神经元。在此，我们测试了肉桂醛诱发的小鼠和豚鼠感觉神经元反应对孔道阻断剂钌红（RuR）的敏感性。
典型的TRPA1选择性激动剂肉桂醛在从小鼠和豚鼠分离的三叉神经元中引起强烈的钙通量。RuR在30 nM时有效抑制小鼠神经元中肉桂醛诱发的反应，3 μM时完全阻断。相比之下，3 μM RuR仅部分抑制豚鼠神经元的反应。我们得出结论，与小鼠TRPA1相比，RuR对豚鼠TRPA1的亲和力降低。本研究为与药物开发相关的动物模型中TRPA1配体亲和力差异提供了进一步证据。
