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

PloS One
Gerald Z ZhuangRoy C Levitt

Abstract

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 i...Continue Reading

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Citations

Dec 1, 2017·Frontiers in Molecular Neuroscience·Benoit LizenFrançoise Gofflot
Aug 12, 2016·Physiological Reviews·Michael J Berridge
Jun 13, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Korynne S RollinsSteven W Copp
May 27, 2017·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Roy C LevittTim Wiltshire
Jan 18, 2020·International Journal of Molecular Sciences·Karolina ŁuczkowskaBogusław Machaliński
Apr 23, 2020·International Journal of Molecular Sciences·Taremekedzwa Allan Sanyanga, Özlem Tastan Bishop
Nov 29, 2020·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Udita UpadhyayRoy C Levitt
Feb 4, 2021·American Journal of Physiology. Gastrointestinal and Liver Physiology·Yuta FujiwaraNobuya Inagaki
Sep 9, 2021·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Korynne S RollinsSteven W Copp

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Methods Mentioned

BETA
PCR
column chromatography
protein collection
transfections
transfection
Assay

Software Mentioned

GENEART
ImageJ

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