Modulation of the trafficking efficiency and functional properties of ATP-sensitive potassium channels through a single amino acid in the sulfonylurea receptor

Etienne A. Cartier, Shen Shu, Show Ling Shyng

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Mutations in the sulfonylurea receptor 1 (SUR1), a subunit of ATP-sensitive potassium (KATP) channels, cause familial hyperinsulinism. One such mutation, deletion of phenylalanine 1388 (ΔPhe-1388), leads to defects in both trafficking and MgADP response of KATP channels. Here we investigated the biochemical features of Phe-1388 that control the proper trafficking and function of KATP channels by substituting the residue with all other 19 amino acids. Whereas surface expression is largely dependent on hydrophobicity, channel response to MgADP is governed by multiple factors and involves the detailed architecture of the amino acid side chain. Thus, structural features in SUR1 required for proper channel function are distinct from those required for correct protein trafficking. Remarkably, replacing Phe-1388 by leucine profoundly alters the physiological and pharmacological properties of the channel. The F1388L-SUR1 channel has increased sensitivity to MgADP and metabolic inhibition, decreased sensitivity to glibenclamide, and responds to both diazoxide and pinacidil. Because this conservative amino acid substitution occurs in the SUR2A and SUR2B isoforms, the mutation provides a mechanism by which functional diversities in KATP channels are generated.

Original languageEnglish (US)
Pages (from-to)7081-7090
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number9
DOIs
StatePublished - Feb 28 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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