Copyright © 2006, European Society of Cardiology
Insulin potentiates TRPC3-mediated cation currents in normal but not in insulin-resistant mouse cardiomyocytes
aDepartment of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
bCenter for Molecular Medicine, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden
* Corresponding author. Tel.: +46 8 524 872 53; fax: +46 8 32 70 26. Email address: hakan.westerblad{at}ki.se
Objective: Recent studies show that bioactive lipids alter intracellular Ca2+ handling of cardiac cells differently in normal and insulin-resistant cardiomyocytes. In the present study we measured non-selective cation currents (NSCC) focusing on the interaction between insulin, the bioactive lipid diacylglycerol (DAG) and canonical transient receptor potential 3 (TRPC3) channels.
Methods: Whole cell patch-clamp was used to measure NSCC in ventricular cardiomyocytes isolated from adult wild-type (WT) and insulin resistant, obese ob/ob mice. Western blot, immunoprecipitation and immunofluorescence staining were used to study the concentration and cellular distribution of TRPC3 channels.
Results: Application of the membrane permeable DAG analogue (OAG, 30 µM) induced an NSCC, which was 
40% smaller in ob/ob than in WT cardiomyocytes. Insulin induced a small NSCC with similar amplitude in ob/ob and WT cells. Pretreatment with insulin (60 nM) increased the OAG-induced NSCC in WT (by 50%) but not in ob/ob cells. OAG-induced currents were inhibited by adding anti-TRPC3 antibodies to the patch pipette solution. The expression of TRPC3 was lower in ob/ob than in WT cardiomyocytes. TRPC3 was detected in glucose transporter 4 (GLUT4) immunoprecipitates. Insulin exposure resulted in a translocation of TRPC3 to the plasma membrane in WT but not in ob/ob cardiomyocytes.
Conclusions: Insulin-resistant ob/ob cardiomyocytes showed decreases in DAG-mediated NSCC, which were accompanied by decreased TRPC3 expression and defective insulin-mediated trafficking of this protein.
KEYWORDS Insulin resistance; Lipid signaling; TRPC channels; Cellular calcium; Type 2 diabetes; Obesity; Patch clamp
Time for primary review 35 days
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