Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels

Gregory M. Martin, Pei Chun Chen, Prasanna Devaraneni, Show-Ling Shyng

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

ATP-sensitive potassium (KATP) channels link cell metabolism to membrane excitability and are involved in a wide range of physiological processes including hormone secretion, control of vascular tone, and protection of cardiac and neuronal cells against ischemic injuries. In pancreatic β-cells, KATP channels play a key role in glucose-stimulated insulin secretion, and gain or loss of channel function results in neonatal diabetes or congenital hyperinsulinism, respectively. The β-cell KATP channel is formed by co-assembly of four Kir6.2 inwardly rectifying potassium channel subunits encoded by KCNJ11 and four sulfonylurea receptor 1 subunits encoded by ABCC8. Many mutations in ABCC8 or KCNJ11 cause loss of channel function, thus, congenital hyperinsulinism by hampering channel biogenesis and hence trafficking to the cell surface. The trafficking defects caused by a subset of these mutations can be corrected by sulfonylureas, KATP channel antagonists that have long been used to treat type 2 diabetes. More recently, carbamazepine, an anticonvulsant that is thought to target primarily voltage-gated sodium channels has been shown to correct KATP channel trafficking defects. This article reviews studies to date aimed at understanding the mechanisms by which mutations impair channel biogenesis and trafficking and the mechanisms by which pharmacological ligands overcome channel trafficking defects. Insight into channel structure-function relationships and therapeutic implications from these studies are discussed.

Original languageEnglish (US)
Article numberArticle 386
JournalFrontiers in Physiology
Volume4 DEC
DOIs
StatePublished - 2013

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KATP Channels
Congenital Hyperinsulinism
Pharmacology
Mutation
Sulfonylurea Receptors
Physiological Phenomena
Voltage-Gated Sodium Channels
Inwardly Rectifying Potassium Channel
Carbamazepine
Anticonvulsants
Type 2 Diabetes Mellitus
Blood Vessels
Hormones
Insulin
Ligands
Glucose
Membranes
Wounds and Injuries

Keywords

  • ATP-sensitive potassium channel
  • Carbamazepine
  • Congenital hyperinsulinism (CHI)
  • Pharmacological chaperone
  • Sulfonylurea

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels. / Martin, Gregory M.; Chen, Pei Chun; Devaraneni, Prasanna; Shyng, Show-Ling.

In: Frontiers in Physiology, Vol. 4 DEC, Article 386, 2013.

Research output: Contribution to journalArticle

Martin, Gregory M. ; Chen, Pei Chun ; Devaraneni, Prasanna ; Shyng, Show-Ling. / Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels. In: Frontiers in Physiology. 2013 ; Vol. 4 DEC.
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