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  • The EMBO Journal (2006) 25, 4605 - 4614
  • doi:10.1038/sj.emboj.7601321

Published online: 14 September 2006

Metabolic regulation of sodium–calcium exchange by intracellular acyl CoAs

Michael J Riedel1,a, István Baczkó1,2,a, Gavin J Searle1,a, Nicola Webster1, Matthew Fercho1, Lynn Jones1, Jessica Lang1, Jonathan Lytton3, Jason RB Dyck1 and Peter E Light1

  1. Departments of Pharmacology and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
  2. Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical Center, University of Szeged, Szeged, Hungary
  3. Departments of Biochemistry & Molecular Biology and Physiology & Biophysics, University of Calgary, Alberta, Canada

Correspondence to:

Peter E Light, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 9-58 Medical Sciences Bldg, Edmonton, Edmonton, Alberta, Canada T6G 2H7. Tel.: +1 780 492 0638; Fax: +1 780 492 4325; E-mail: peter.light@ualberta.ca

aThese authors contributed equally to this work

Received 20 February 2006; Accepted 9 August 2006

The sodium–calcium exchanger (NCX) is a critical mediator of calcium homeostasis. In the heart, NCX1 predominantly operates in forward mode to extrude Ca2+; however, reverse-mode NCX1 activity during ischemia/reperfusion (IR) contributes to Ca2+ loading and electrical and contractile dysfunction. IR injury has also been associated with altered fat metabolism and accumulation of long-chain acyl CoA esters. Here, we show that acyl CoAs are novel, endogenous activators of reverse-mode NCX1 activity, exhibiting chain length and saturation dependence, with longer chain saturated acyl moieties being the most effective NCX1 activators. These results implicate dietary fat composition as a plausible determinant of IR injury. We further show that acyl CoAs may interact directly with the XIP (exchanger inhibitory peptide) sequence, a known region of anionic lipid modulation, to dynamically regulate NCX1 activity and Ca2+ homeostasis. Additionally, our findings have broad implications for the coupling of Ca2+ homeostasis to fat metabolism in a variety of tissues.

  • Keywords:

    • acyl CoA,
    • fat metabolism,
    • ischemia/reperfusion injury,
    • NCX1,
    • sodium–calcium exchange