Nociceptor-enriched CAPS1 isoform couples to CaV2.2 channels and underlies inflammatory pain hypersensitivity

Authors
Melissa Daeschner, Emilio Román Mustafa, Andi Morgan, Quiana Tyss Mosley, Eduardo Javier López Soto


Lab

Journal
bioRxiv

Abstract

Abstract

How broadly expressed presynaptic proteins acquire the cell-type specificity needed to couple to CaV2 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 CaV2.2 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 CaV2.2 currents, whereas disruption of the e16a-encoded sequence blocked this effect and reduced endogenous CaV2.2 currents in nociceptors. Conditional Cadps deletion in Trpv1-lineage nociceptors similarly reduced CaV2.2 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 CaV2.2 coupling and underlies inflammatory pain hypersensitivity.

Keywords/Topics
inflammatory pain hypersensitivity abstract; behavior; intrathecal delivery; nociceptor-enriched caps1 isoform couples; presynaptic proteins; defined neurons; alternative splicing; cadps; caps1; nociceptor-selective

Source :

https://www.biorxiv.org/content/10.64898/2026.05.23.727326.abstract

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