Facilitation of Cav3.2 channel gating in pain pathways reveals a novel mechanism of serum-induced hyperalgesia

Sanner, K.; Kawell, S.; Evans, G. J.; Elekovic, V.; Walz, M.; Joksimovic, S. L.; Joksimovic, S. M.; Donald, R. R.; Tomic, M.; Orestes, P.; Feseha, S.; Dedek, A.; Ghodsi, S. M.; Fallon, I. P.; Lee, J.; Hwang, S. M.; Hong, S. J.; Covey, D. F.; Romano, C.; Timic Stamenic, T.; Chemin, J.; Bourinet, E.; Zorumski, C. F.; Mayer, J. P.; Stowell, M. H. B.; Hildebrand, M. E.; Eisenmesser, E. Z.; Jevtovic-Todorovic, V.; Todorovic, S. M.

doi:10.1101/2025.01.03.631165

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bioRxiv · 10.1101/2025.01.03.631165

Facilitation of Cav3.2 channel gating in pain pathways reveals a novel mechanism of serum-induced hyperalgesia

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Abstract

The CaV3.2 isoform of T-type voltage-gated calcium channels plays a crucial role in regulating the excitability of nociceptive neurons; the endogenous molecules that modulate its activity, however, remain poorly understood. Here, we used serum proteomics and patch-clamp physiology to discover a novel peptide albumin (1-26) that facilitates channel gating by chelating trace metals that tonically inhibit CaV3.2 via H191 residue. Importantly, serum also potently modulated T-currents in human and rodent dorsal root ganglion (DRG) neurons. In vivo pain studies revealed that injections of serum and albumin (1-26) peptide resulted in robust mechanical and heat hypersensitivity. This hypersensitivity was abolished with a T-channel inhibitor, in CaV3.2 null mice and in CaV3.2 H191Q knock-in mice. The discovery of endogenous chelators of trace metals in the serum deepens our understanding of the role of CaV3.2 channels in neuronal hyperexcitability and may facilitate the design of novel analgesics with unique mechanisms of action.

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Sanner, K., Kawell, S., Evans, G. J., Elekovic, V., Walz, M., Joksimovic, S. L., Joksimovic, S. M., Donald, R. R., Tomic, M., Orestes, P., Feseha, S., Dedek, A., Ghodsi, S. M., Fallon, I. P., Lee, J., Hwang, S. M., Hong, S. J., Covey, D. F., Romano, C., Timic Stamenic, T., Chemin, J., Bourinet, E., Zorumski, C. F., Mayer, J. P., Stowell, M. H. B., Hildebrand, M. E., Eisenmesser, E. Z., Jevtovic-Todorovic, V., Todorovic, S. M.. 2025-01-03. Facilitation of Cav3.2 channel gating in pain pathways reveals a novel mechanism of serum-induced hyperalgesia. https://doi.org/10.1101/2025.01.03.631165

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