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Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway.

Publication ,  Journal Article
Zhuang, GZ; Keeler, B; Grant, J; Bianchi, L; Fu, ES; Zhang, YP; Erasso, DM; Cui, J-G; Wiltshire, T; Li, Q; Hao, S; Sarantopoulos, KD ...
Published in: PLoS One
2015

Calcium dysregulation is causally linked with various forms of neuropathology including seizure disorders, multiple sclerosis, Huntington's disease, Alzheimer's, spinal cerebellar ataxia (SCA) and chronic pain. Carbonic anhydrase-8 (Car8) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates intracellular calcium release fundamental to critical cellular functions including neuronal excitability, neurite outgrowth, neurotransmitter release, mitochondrial energy production and cell fate. In this report we test the hypothesis that Car8 regulation of ITPR1 and cytoplasmic free calcium release is critical to nociception and pain behaviors. We show Car8 null mutant mice (MT) exhibit mechanical allodynia and thermal hyperalgesia. Dorsal root ganglia (DRG) from MT also demonstrate increased steady-state ITPR1 phosphorylation (pITPR1) and cytoplasmic free calcium release. Overexpression of Car8 wildtype protein in MT nociceptors complements Car8 deficiency, down regulates pITPR1 and abolishes thermal and mechanical hypersensitivity. We also show that Car8 nociceptor overexpression alleviates chronic inflammatory pain. Finally, inflammation results in downregulation of DRG Car8 that is associated with increased pITPR1 expression relative to ITPR1, suggesting a possible mechanism of acute hypersensitivity. Our findings indicate Car8 regulates the ITPR1-cytosolic free calcium pathway that is critical to nociception, inflammatory pain and possibly other neuropathological states. Car8 and ITPR1 represent new therapeutic targets for chronic pain.

Duke Scholars

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2015

Volume

10

Issue

3

Start / End Page

e0118273

Location

United States

Related Subject Headings

  • Phosphorylation
  • Nociception
  • Neurons
  • Nerve Tissue Proteins
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Long-Term Potentiation
  • Inositol 1,4,5-Trisphosphate Receptors
 

Citation

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Zhuang, G. Z., Keeler, B., Grant, J., Bianchi, L., Fu, E. S., Zhang, Y. P., … Levitt, R. C. (2015). Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway. PLoS One, 10(3), e0118273. https://doi.org/10.1371/journal.pone.0118273
Zhuang, Gerald Z., Benjamin Keeler, Jeff Grant, Laura Bianchi, Eugene S. Fu, Yan Ping Zhang, Diana M. Erasso, et al. “Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway.PLoS One 10, no. 3 (2015): e0118273. https://doi.org/10.1371/journal.pone.0118273.
Zhuang GZ, Keeler B, Grant J, Bianchi L, Fu ES, Zhang YP, et al. Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway. PLoS One. 2015;10(3):e0118273.
Zhuang, Gerald Z., et al. “Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway.PLoS One, vol. 10, no. 3, 2015, p. e0118273. Pubmed, doi:10.1371/journal.pone.0118273.
Zhuang GZ, Keeler B, Grant J, Bianchi L, Fu ES, Zhang YP, Erasso DM, Cui J-G, Wiltshire T, Li Q, Hao S, Sarantopoulos KD, Candiotti K, Wishnek SM, Smith SB, Maixner W, Diatchenko L, Martin ER, Levitt RC. Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway. PLoS One. 2015;10(3):e0118273.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2015

Volume

10

Issue

3

Start / End Page

e0118273

Location

United States

Related Subject Headings

  • Phosphorylation
  • Nociception
  • Neurons
  • Nerve Tissue Proteins
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Long-Term Potentiation
  • Inositol 1,4,5-Trisphosphate Receptors