Single residue (K332A) substitution in Kir6.2 abolishes the stimulatory effect of long-chain acyl-CoA esters: Indications for a long-chain acyl-CoA ester binding motif

R. Bränström, I. B. Leibiger, B. Leibiger, G. Klement, J. Nilsson, P. Århem, Craig A Aspinwall, B. E. Corkey, O. Larsson, P. O. Berggren

Research output: Contribution to journalArticle

13 Scopus citations


Aims/hypothesis: The pancreatic beta cell ATP-sensitive potassium (K ATP) channel, composed of the pore-forming α subunit Kir6.2, a member of the inward rectifier K+channel family, and the regulatory β subunit sulfonylurea receptor 1 (SUR1), a member of the ATP-binding cassette superfamily, couples the metabolic state of the cell to electrical activity. Several endogenous compounds are known to modulate KATP channel activity, including ATP, ADP, phosphatidylinositol diphosphates and long-chain acyl coenzyme A (LC-CoA) esters. LC-CoA esters have been shown to interact with Kir6.2, but the mechanism and binding site(s) have yet to be identified. Materials and methods: Using multiple sequence alignment of known acyl-CoA ester interacting proteins, we were able to identify four conserved amino acid residues that could potentially serve as an acyl-CoA ester-binding motif. The motif was also recognised in the C-terminal region of Kir6.2 (R311-332) but not in SUR1. Results: Oocytes expressing Kir6.2ΔC26 K332A repeatedly generated K+currents in inside-out membrane patches that were sensitive to ATP, but were only weakly activated by 1 μmol/l palmitoyl-CoA ester. Compared with the control channel (Kir6.2ΔC26), Kir6.2ΔC26 K332A displayed unaltered ATP sensitivity but significantly decreased sensitivity to palmitoyl-CoA esters. Coexpression of Kir6.2ΔC26 K332A and SUR1 revealed slightly increased activation by palmitoyl-CoA ester but significantly decreased activation by the acyl-CoA esters compared with the wild-type KATP channel and Kir6.2ΔC26+SUR1. Computational modelling, using the crystal structure of KirBac1.1, suggested that K332 is located on the intracellular domain of Kir6.2 and is accessible to intracellular modulators such as LC-CoA esters. Conclusions/interpretation: These results verify that LC-CoA esters interact at the pore-forming subunit Kir6.2, and on the basis of these data we propose an acyl-CoA ester binding motif located in the C-terminal region.

Original languageEnglish (US)
Pages (from-to)1670-1677
Number of pages8
Issue number8
Publication statusPublished - Aug 2007



  • Basic Science
  • Beta cell signal transduction
  • Cells
  • Lipids/lipoproteins
  • Other techniques

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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