Facilitation of Ca V 3.2 channel gating in pain pathways reveals a novel mechanism of serum-induced hyperalgesia.

The Ca V 3.2 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 Ca V 3.2 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 Ca V 3.2 null mice and in Ca V 3.2 H191Q knock-in mice. The discovery of endogenous chelators of trace metals in the serum deepens our understanding of the role of Ca V 3.2 channels in neuronal hyperexcitability and may facilitate the design of novel analgesics with unique mechanisms of action.