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Pharmacological targeting of the mitochondrial phosphatase PTPMT1.

Publication ,  Journal Article
Doughty-Shenton, D; Joseph, JD; Zhang, J; Pagliarini, DJ; Kim, Y; Lu, D; Dixon, JE; Casey, PJ
Published in: J Pharmacol Exp Ther
May 2010

The dual-specificity protein tyrosine phosphatases (PTPs) play integral roles in the regulation of cell signaling. There is a need for new tools to study these phosphatases, and the identification of inhibitors potentially affords not only new means for their study, but also possible therapeutics for the treatment of diseases caused by their dysregulation. However, the identification of selective inhibitors of the protein phosphatases has proven somewhat difficult. PTP localized to mitochondrion 1 (PTPMT1) is a recently discovered dual-specificity phosphatase that has been implicated in the regulation of insulin secretion. Screening of a commercially available small-molecule library yielded alexidine dihydrochloride, a dibiguanide compound, as an effective and selective inhibitor of PTPMT1 with an in vitro concentration that inhibits response by 50% of 1.08 microM. A related dibiguanide analog, chlorhexidine dihydrochloride, also significantly inhibited PTPMT1, albeit with lower potency, while a monobiguanide analog showed very weak inhibition. Treatment of isolated rat pancreatic islets with alexidine dihydrochloride resulted in a dose-dependent increase in insulin secretion, whereas treatment of a pancreatic beta-cell line with the drug affected the phosphorylation of mitochondrial proteins in a manner similar to genetic inhibition of PTPMT1. Furthermore, knockdown of PTPMT1 in rat islets rendered them insensitive to alexidine dihydrochloride treatment, providing evidence for mechanism-based activity of the inhibitor. Taken together, these studies establish alexidine dihydrochloride as an effective inhibitor of PTPMT1, both in vitro and in cells, and support the notion that PTPMT1 could serve as a pharmacological target in the treatment of type II diabetes.

Duke Scholars

Published In

J Pharmacol Exp Ther

DOI

EISSN

1521-0103

Publication Date

May 2010

Volume

333

Issue

2

Start / End Page

584 / 592

Location

United States

Related Subject Headings

  • Rats, Wistar
  • Rats
  • Phosphorylation
  • Pharmacology & Pharmacy
  • Mitochondrial Proteins
  • Mitochondria
  • Islets of Langerhans
  • Insulin Secretion
  • Insulin
  • Immunoblotting
 

Citation

APA
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ICMJE
MLA
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Doughty-Shenton, D., Joseph, J. D., Zhang, J., Pagliarini, D. J., Kim, Y., Lu, D., … Casey, P. J. (2010). Pharmacological targeting of the mitochondrial phosphatase PTPMT1. J Pharmacol Exp Ther, 333(2), 584–592. https://doi.org/10.1124/jpet.109.163329
Doughty-Shenton, Dahlia, James D. Joseph, Ji Zhang, David J. Pagliarini, Youngjun Kim, Danhong Lu, Jack E. Dixon, and Patrick J. Casey. “Pharmacological targeting of the mitochondrial phosphatase PTPMT1.J Pharmacol Exp Ther 333, no. 2 (May 2010): 584–92. https://doi.org/10.1124/jpet.109.163329.
Doughty-Shenton D, Joseph JD, Zhang J, Pagliarini DJ, Kim Y, Lu D, et al. Pharmacological targeting of the mitochondrial phosphatase PTPMT1. J Pharmacol Exp Ther. 2010 May;333(2):584–92.
Doughty-Shenton, Dahlia, et al. “Pharmacological targeting of the mitochondrial phosphatase PTPMT1.J Pharmacol Exp Ther, vol. 333, no. 2, May 2010, pp. 584–92. Pubmed, doi:10.1124/jpet.109.163329.
Doughty-Shenton D, Joseph JD, Zhang J, Pagliarini DJ, Kim Y, Lu D, Dixon JE, Casey PJ. Pharmacological targeting of the mitochondrial phosphatase PTPMT1. J Pharmacol Exp Ther. 2010 May;333(2):584–592.
Journal cover image

Published In

J Pharmacol Exp Ther

DOI

EISSN

1521-0103

Publication Date

May 2010

Volume

333

Issue

2

Start / End Page

584 / 592

Location

United States

Related Subject Headings

  • Rats, Wistar
  • Rats
  • Phosphorylation
  • Pharmacology & Pharmacy
  • Mitochondrial Proteins
  • Mitochondria
  • Islets of Langerhans
  • Insulin Secretion
  • Insulin
  • Immunoblotting