Ca V3.2 links mast cells, tryptase and pain

Abstract Hereditary a-tryptasemia (HaT) is a genetic trait defined by elevated serum tryptase caused by increased TPSAB1 copy number and associated with multiple phenotypes including pain. CACNA1H encoding the voltage-gated calcium channel Ca V3.2 overlaps the tryptase locus where a partial gain-of-function (GOF) haplotype containing 3 linked variants has been shown to be co-inherited with HaT in ~2/3 of individuals. While Ca V3.2 is expressed in neurons where it contributes to pain perception, expression has also been observed in other cells. Mast cells are the principal source of tryptase, exist in proximity with nerves, and have been implicated in pain sensation. We set out to investigate links between these variants, mast cells, and pain. Performing tryptase and CACNA1H genotyping via ddPCR in a cohort of fibromyalgia patients we found that HaT was enriched compared to the general population (p=0.029). However, the CACNA1H haplotype was universally present, suggesting these variants were driving the association. In support of this observation, enrichment of the GOF variants was also observed among those without HaT. Using flow cytometry, immunoblotting, ddPCR, and immunofluorescence, we found LAD2 cells express Ca V3.2 where it co-localizes at the cell surface with calnexin and confirmed expression in primary cultured human mast cells. To our knowledge, this is the first report of a voltage-gated calcium channel on mast cells. While calcium flux is critical for mast cell activation, mechanisms driving voltage-gated channel activation remain to be elucidated. Future studies will help unravel the mechanisms linking mast cell activation and pain pathways enabling the development of therapies for these commonly linked clinical phenotypes. Supported by grant from DIR NIAID NIH, grant: ZIA AI001192