Pharmacological modulation of TRPV2 enhances migration and induces Immunoglobulin E (IgE)-independent degranulation of mast cells

Transient receptor potential vanilloid 2 (TRPV2) is highly expressed in immune cells, including mast cells, yet its functional role in mast cell physiology remains incompletely understood. Given the increasing global prevalence of immune disorders, elucidating TRPV2-mediated mechanisms may uncover novel therapeutic approaches. Using fluorometric Ca 2+ influx assays and electrophysiological patch-clamp recordings, this study analyzes synergistic effects of the TRPV2 activators AV2-1, cannabidiol and probenecid. Superadditive TRPV2 activation was observed upon co-application of probenecid and cannabidiol, as well as by the combination of AV2-1 and cannabidiol. The effects of the activators were validated in primary mouse bone marrow-derived mast cells (mBMMCs) and the human mast cell-like cell line HMC-1.2. Activation of TRPV2 by the cannabidiol/probenecid combination or by AV2-1 alone induced mBMMC degranulation, as assessed by β-hexosaminidase release, histamine secretion, and increased CD63 surface expression measured by flow cytometry, without evidence of long-term cytotoxicity. TRPV2-dependent degranulation was additive to FcεRI-mediated responses induced by anti-DNP-IgE/DNP-HSA stimulation, indicating mechanistically distinct signaling pathways. In addition, TRPV2 activation enhanced mBMMC migration. All observed effects were abolished by the TRPV2 inhibitor IV2-1 or genetic deletion of TRPV2 in transwell migration assays. These findings demonstrate that pharmacological activation of TRPV2 modulates mast cell effector functions and migration, supporting a role for TRPV2 as an immunomodulatory ion channel and a potential therapeutic target in immune system-related pathologies.