Nociceptor-enriched CAPS1 isoform couples to Ca_V2.2 channels and underlies inflammatory pain hypersensitivity

How broadly expressed presynaptic proteins acquire the cell-type specificity needed to couple to Ca_V2 channels in defined neurons, and whether this specialization contributes to behavior, remains poorly understood. We show that alternative splicing of Cadps, encoding the vesicle-priming factor CAPS1, generates nociceptor-selective Ca_V2.2 regulation and underlies inflammatory pain hypersensitivity. Although Cadps is comparably expressed across dorsal root ganglion neurons, exon-resolution analysis identified exon 16a, a conserved 23-amino-acid cassette, as selectively enriched in nociceptors. The e16a-containing CAPS1 isoform, but not CAPS1 lacking e16a, enhanced recombinant Ca_V2.2 currents, whereas disruption of the e16a-encoded sequence blocked this effect and reduced endogenous Ca_V2.2 currents in nociceptors. Conditional Cadps deletion in Trpv1-lineage nociceptors similarly reduced Ca_V2.2 currents and attenuated capsaicin-evoked inflammatory hypersensitivity while sparing baseline sensitivity, an effect replicated by intrathecal delivery of an exon 16a-derived peptide. Alternative splicing of a presynaptic partner protein thus confers cell-type-specific Ca_V2.2 coupling and underlies inflammatory pain hypersensitivity.