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Diabetes. 2018 May;67(5):849-860. doi: 10.2337/db17-1433. Epub 2018 Feb 12.

Regulation of KATP Channel Trafficking in Pancreatic β-Cells by Protein Histidine Phosphorylation.

Author information

1
Division of Nephrology, New York University Langone Medical Center, New York, NY.
2
The Helen L. and Martin S. Kimmel Center for Biology and Medicine, New York University Langone Medical Center, New York, NY.
3
Skirball Institute for Biomolecular Medicine Skirball Institute, New York University Langone Medical Center, New York, NY.
4
Department of Pediatrics, New York University Langone Medical Center, New York, NY.
5
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA.
6
Division of Nephrology, New York University Langone Medical Center, New York, NY edward.skolnik@nyumc.org.

Abstract

Protein histidine phosphatase 1 (PHPT-1) is an evolutionarily conserved 14-kDa protein that dephosphorylates phosphohistidine. PHPT-1-/- mice were generated to gain insight into the role of PHPT-1 and histidine phosphorylation/dephosphorylation in mammalian biology. PHPT-1-/- mice exhibited neonatal hyperinsulinemic hypoglycemia due to impaired trafficking of KATP channels to the plasma membrane in pancreatic β-cells in response to low glucose and leptin and resembled patients with congenital hyperinsulinism (CHI). The defect in KATP channel trafficking in PHPT-1-/- β-cells was due to the failure of PHPT-1 to directly activate transient receptor potential channel 4 (TRPC4), resulting in decreased Ca2+ influx and impaired downstream activation of AMPK. Thus, these studies demonstrate a critical role for PHPT-1 in normal pancreatic β-cell function and raise the possibility that mutations in PHPT-1 and/or TRPC4 may account for yet to be defined cases of CHI.

PMID:
29440278
PMCID:
PMC5909995
DOI:
10.2337/db17-1433
[Indexed for MEDLINE]
Free PMC Article

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