Reversion mutation of cDNA CA8-204 minigene construct produces a truncated functional peptide that regulates calcium release in vitro and produces profound analgesia in vivo.

Journal Article (Journal Article)

Intracellular calcium is critical in orchestrating neuronal excitability and analgesia. Carbonic anhydrase-8 (CA8) regulates intracellular calcium signaling through allosteric inhibition of neuronal inositol trisphosphate receptor 1 (ITPR1) to produce profound analgesia. Recently, we reported the "G" allele at rs6471859 represents cis-eQTL regulating alternative splicing of a 1697 bp transcript (CA8-204G) with a retained intron, alternative polyadenylation site and a new stop codon producing a functional 26 kDa peptide with an extended exon 3. In this study we show the reversion mutation (G to C) at rs6471859 within the CA8-204G expression vector also produced a stable 1697 bp transcript (CA8-204C) coding for a smaller peptide (~ 22 kDa) containing only the first three CA8 exons. Surprisingly, this peptide inhibited ITPR1 (pITPR1) activation, ITPR1-mediated calcium release in vitro; and produced profound analgesia in vivo. This is the first report showing CA8-204C codes for a functional peptide sufficient to regulate calcium signaling and produce profound analgesia.

Full Text

Duke Authors

Cited Authors

  • Upadhyay, U; Zhuang, GZ; Diatchenko, L; Parisien, M; Kang, Y; Sarantopoulos, KD; Martin, ER; Smith, SB; Maixner, W; Levitt, RC

Published Date

  • December 2020

Published In

Volume / Issue

  • 31 / 9-12

Start / End Page

  • 287 - 294

PubMed ID

  • 33247772

Electronic International Standard Serial Number (EISSN)

  • 1432-1777

Digital Object Identifier (DOI)

  • 10.1007/s00335-020-09848-y


  • eng

Conference Location

  • United States