Journal Article Preprint Epublish
PubMed: 39763894 DOI: 10.1101/2024.12.27.630513
Truncated TrkB: The predominant TrkB Isoform in Nociceptors.
bioRxiv
Authors: Jaclyn Merlo, Chang Fang-Mei, Michael Tran, Jessie Alfaro, Tarek Ibrahim, Ping Wu, Shivani Ruparel
Affiliations
- 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.
- Department of Microbiology and Immunology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
- Integrated Biomedical Sciences (IBMS) Program, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229 USA.
- Department of Pharmacology and Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Abstract
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.
MeSH
Neurons, Pain, Protein Isoforms, Calcium, Nociceptors, Sensory Receptor Cells