Journal
DIABETES
Volume 67, Issue 5, Pages 849-860Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-1433
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Funding
- National Institutes of Health [1R01-DK-098517-01A1, R01-GM-099873, R01-AI-080583]
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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 K-ATP channels to the plasma membrane in pancreatic beta-cells in response to low glucose and leptin and resembled patients with congenital hyperinsulinism (CHI). The defect in K-ATP channel trafficking in PHPT-1(-/-) beta-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 beta-cell function and raise the possibility that mutations in PHPT-1 and/or TRPC4 may account for yet to be defined cases of CHI.
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