Metabolic regulation of sodium-calcium exchange by intracellular acyl CoAs.
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.
Riedel
Michael J
MJ
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Baczkó
István
I
Searle
Gavin J
GJ
Webster
Nicola
N
Fercho
Matthew
M
Jones
Lynn
L
Lang
Jessica
J
Lytton
Jonathan
J
Dyck
Jason R B
JR
Light
Peter E
PE
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*
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