BPS2026 – Targeting the TRPV1-calmodulin interaction: A potential strategy to treat inflammatory and neuropathic pain

Pain, whether acute or chronic, remains a major therapeutic challenge. Among ion channels involved in nociception, TRPV1 (transient receptor potential anilloid 1) acts as a polymodal sensor of noxious stimuli such as heat, acidic pH, and capsaicin. Expressed in nociceptors, TRPV1 amplifies pain signals and represents a promising target for novel analgesics. However, current strategies using agonists or antagonists often induce adverse effects, including impaired thermoregulation and sensory irritation, which limit their clinical application. TRPV1 function is regulated by calmodulin (CaM), a ubiquitous calcium-sensing protein. Classically described as a negative regulator promoting TRPV1 desensitization, this model has recently been challenged. Using bioluminescence resonance energy transfer (BRET)-based sensors, we found that CaM inhibitors unexpectedly reduce TRPV1 activity, suggesting a positive regulatory role of CaM. To probe this mechanism, we designed genetically encoded peptides mimicking TRPV1 sequences that interact with CaM. Three independent BRET assays showed that peptides targeting TRPV1’s C-terminal domains reduce its membrane expression, mimicking capsaicin’s effects. In contrast, a peptide targeting the N-terminal interaction site stabilized TRPV1 at the plasma membrane. These results reveal a bidirectional regulation of TRPV1 by CaM depending on the interaction domain. We are now testing synthetic peptides developed in collaboration with chemists (X-Pharma, Paris) to confirm these effects. The next step will assess their potential as topical treatments in murine models of localized pain. Together, our findings highlight TRPV1-CaM interaction as an unexplored therapeutic target and open potential new avenues for pain management strategies.