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

Srivastava, Shekhar; Zhai Li; Soomro, Irfana; Ying Sun; Jianhui Wang; Li Bao; Coetzee, William A.; Stanley, Charles A.; Chonghong Li; Skolnik, Edward Y.; Li, Zhai; Sun, Ying; Wang, Jianhui; Bao, Li; Li, Chonghong

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.

ADENOSINE triphosphate; POTASSIUM channels; PROTEINS; HISTIDINE; PHOSPHATASES; DEPHOSPHORYLATION; CALCIUM metabolism; HISTIDINE metabolism; ANIMAL experimentation; ANIMAL populations; BIOLOGICAL models; BIOLOGICAL transport; CARRIER proteins; CYTOLOGICAL techniques; HYPERINSULINISM; HYPOGLYCEMIA; ISLANDS of Langerhans; MICE; PHOSPHORYLATION; RESEARCH funding; MEMBRANE transport proteins; GENETICS

Diabetes, 2018, Vol 67, Issue 5, p849

0012-1797

Academic Journal

10.2337/db17-1433