Merlo Jaclyn, Fang-Mei Chang, Tran Michael, Alfaro Jessie, Ibrahim Tarek, Wu Ping, Ruparel Shivani
Center for Pain Therapeutics and Addiction Research, School of Dentistry, University of Texas Health San Antonio, Texas, 78229, USA.
Department of Endodontics, School of Dentistry, University of Texas Health San Antonio, Texas, 78229, USA.
bioRxiv. 2024 Dec 27:2024.12.27.630513. doi: 10.1101/2024.12.27.630513.
Truncated TrkB (TrkBT1), traditionally considered a dominant-negative regulator of full-length TrkB (TrkBTK+), remains poorly understood in peripheral sensory neurons, particularly nociceptors. Furthermore, sensory neuronal TrkB expression and function has been traditionally associated with non-nociceptive neurons, particularly Aδ low-threshold mechanoreceptors. This study challenges prevailing assumptions by demonstrating that TrkBT1 is the predominant TrkB isoform expressed in sensory neurons and plays a functional role in modulating neuronal activity. We demonstrate that TrkBT1 is the predominant isoform expressed in nociceptors, identified by markers such as TRPV1, TRPA1, TRPM8 and 5HT3A, as well as non-nociceptors, while the full-length isoform (TrkBTK+) is restricted to non-nociceptive subpopulation. Functionally, we show that acute application of BDNF induces modest calcium influx in nociceptors and prolonged BDNF exposure significantly potentiates capsaicin-induced calcium influx, an effect blocked by the TrkB-specific antagonist ANA12. Additionally, BDNF also promotes the survival of both nociceptive and non-nociceptive neurons in culture, an effect dependent on TrkBT1 activity. Our data also reveal that ANA12 inhibits BDNF-mediated neuronal sensitization and survival in a concentration-dependent manner, implicating distinct TrkBT1 signaling pathways in these processes. Collectively, our findings redefine TrkBT1 as a functional modulator of nociceptor activity rather than a passive regulator of full-length TrkB. By uncovering its dual roles in nociceptor sensitization and survival, this study provides new insights into the molecular mechanisms of BDNF/TrkB signaling in pain. Future work evaluating the role of TrkBT1 in sensory biology could offer new perspectives on how this receptor contributes to neuronal function and plasticity during chronic pain conditions.
截短型TrkB（TrkBT1），传统上被认为是全长TrkB（TrkBTK+）的显性负调控因子，在外周感觉神经元，尤其是伤害性感受器中，其作用仍知之甚少。此外，感觉神经元TrkB的表达和功能传统上一直与非伤害性神经元相关，特别是Aδ低阈值机械感受器。本研究通过证明TrkBT1是感觉神经元中表达的主要TrkB异构体，并在调节神经元活动中发挥功能作用，对普遍的假设提出了挑战。我们证明TrkBT1是在伤害性感受器中表达的主要异构体，这些伤害性感受器可通过TRPV1、TRPA1、TRPM8和5HT3A等标记物以及非伤害性感受器来识别，而全长异构体（TrkBTK+）则局限于非伤害性亚群。在功能上，我们表明急性应用脑源性神经营养因子（BDNF）会在伤害性感受器中诱导适度的钙内流，而长时间暴露于BDNF会显著增强辣椒素诱导的钙内流，这一效应被TrkB特异性拮抗剂ANA12阻断。此外，BDNF还能促进培养的伤害性和非伤害性神经元的存活，这一效应依赖于TrkBT1的活性。我们的数据还表明，ANA12以浓度依赖的方式抑制BDNF介导的神经元致敏和存活，这意味着在这些过程中有不同的TrkBT1信号通路。总的来说，我们的研究结果将TrkBT1重新定义为伤害性感受器活动的功能调节因子，而不是全长TrkB的被动调节因子。通过揭示其在伤害性感受器致敏和存活中的双重作用，本研究为BDNF/TrkB信号在疼痛中的分子机制提供了新的见解。未来评估TrkBT1在感觉生物学中作用的工作可能会为该受体在慢性疼痛状态下如何促进神经元功能和可塑性提供新的视角。
