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Papers of the Week

Papers: 28 Nov 2020 - 4 Dec 2020

Animal Studies

2020 Nov 28

Mamm Genome

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.


Upadhyay U, Zhuang GZ, Diatchenko L, Parisien M, Kang Y, Sarantopoulos KD, Martin ER, Smith SB, Maixner W, Levitt RC
Mamm Genome. 2020 Nov 28.
PMID: 33247772.


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 (CA8-204) 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 CA8-204 expression vector also produced a stable 1697 bp transcript (CA8-204) 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 CA8-204 codes for a functional peptide sufficient to regulate calcium signaling and produce profound analgesia.