title: Metabolic regulation of sodium-calcium exchange by intracellular acyl CoAs.
abstract: The sodium-calcium exchanger (NCX) is a critical mediator of calcium homeostasis. In the heart, NCX1 predominantly operates in forward mode to extrude Ca(2+); however, reverse-mode NCX1 activity during ischemia/reperfusion (IR) contributes to Ca(2+) 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 Ca(2+) homeostasis. Additionally, our findings have broad implications for the coupling of Ca(2+) homeostasis to fat metabolism in a variety of tissues.
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Riedel
authors.forename: István
authors.initials: I
authors.lastname: Baczkó
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Searle
authors.forename: Nicola
authors.initials: N
authors.lastname: Webster
authors.forename: Matthew
authors.initials: M
authors.lastname: Fercho
authors.forename: Lynn
authors.initials: L
authors.lastname: Jones
authors.forename: Jessica
authors.initials: J
authors.lastname: Lang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lytton
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Peter E
authors.initials: PE
authors.lastname: Light
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D000214:Acyl Coenzyme A; D005227:Fatty Acids; D010455:Peptides; D019269:Phosphatidylinositol 4,5-Diphosphate; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; C066745:exchanger inhibitory peptide; D000255:Adenosine Triphosphate; D002118:Calcium