Carbamazepine promotes surface expression of mutant Kir6.2-A28V ATP-sensitive potassium channels by modulating Golgi retention and autophagy

Ching Han Lin, Yu Chi Lin, Shi Bing Yang, Pei Chun Chen

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Pancreatic β-cells express ATP-sensitive potassium (KATP) channels, consisting of octamer complexes containing four sulfonylurea receptor 1 (SUR1) and four Kir6.2 subunits. Loss of KATP channel function causes persistent hyperinsulinemic hypoglycemia of infancy (PHHI), a rare but debilitating condition if not treated. We previously showed that the sodium-channel blocker carbamazepine (Carb) corrects KATP channel surface expression defects induced by PHHI-causing mutations in SUR1. In this study, we show that Carb treatment can also ameliorate the trafficking deficits associated with a recently discovered PHHI-causing mutation in Kir6.2 (Kir6.2-A28V). In human embryonic kidney 293 or INS-1 cells expressing this mutant KATP channel (SUR1 and Kir6.2-A28V), biotinylation and immunostaining assays revealed that Carb can increase surface expression of the mutant KATP channels. We further examined the subcellular distributions of mutant KATP channels before and after Carb treatment; without Carb treatment, we found that mutant KATP channels were aberrantly accumulated in the Golgi apparatus. However, after Carb treatment, coimmunoprecipitation of mutant KATP channels and Golgi marker GM130 was diminished, and KATP staining was also reduced in lysosomes. Intriguingly, Carb treatment also simultaneously increased autophagic flux and p62 accumulation, suggesting that autophagy-dependent degradation of the mutant channel was not only stimulated but also interrupted. In summary, our data suggest that surface expression of Kir6.2-A28V KATP channels is rescued by Carb treatment via promotion of mutant KATP channel exit from the Golgi apparatus and reduction of autophagy-mediated protein degradation.

Original languageEnglish
Article number101904
JournalJournal of Biological Chemistry
Volume298
Issue number5
DOIs
Publication statusPublished - 2022 May 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Carbamazepine promotes surface expression of mutant Kir6.2-A28V ATP-sensitive potassium channels by modulating Golgi retention and autophagy'. Together they form a unique fingerprint.

Cite this