Insulin potentiates TRPC3-mediated cation currents in normal but not in insulin-resistant mouse cardiomyocytes

doi:10.1016/j.cardiores.2006.10.018

Cardiovascular Research 2007 73(2):376-385; doi:10.1016/j.cardiores.2006.10.018

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Insulin potentiates TRPC3-mediated cation currents in normal but not in insulin-resistant mouse cardiomyocytes

Jérémy Fauconnier^a, Johanna T. Lanner^a, Ariane Sultan^b, Shi-Jin Zhang^a, Abram Katz^a, Joseph D. Bruton^a and Håkan Westerblad^a^,*

^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 intracellularCa²⁺ handling of cardiac cells differently in normal and insulin-resistantcardiomyocytes. In the present study we measured non-selectivecation currents (NSCC) focusing on the interaction between insulin,the bioactive lipid diacylglycerol (DAG) and canonical transientreceptor potential 3 (TRPC3) channels.

Methods: Whole cell patch-clamp was used to measure NSCC inventricular cardiomyocytes isolated from adult wild-type (WT)and insulin resistant, obese ob/ob mice. Western blot, immunoprecipitationand immunofluorescence staining were used to study the concentrationand cellular distribution of TRPC3 channels.

Results: Application of the membrane permeable DAG analogue(OAG, 30 µM) induced an NSCC, which was $~$ 40% smallerin ob/ob than in WT cardiomyocytes. Insulin induced a smallNSCC with similar amplitude in ob/ob and WT cells. Pretreatmentwith insulin (60 nM) increased the OAG-induced NSCC inWT (by $~$ 50%) but not in ob/ob cells. OAG-induced currents wereinhibited by adding anti-TRPC3 antibodies to the patch pipettesolution. The expression of TRPC3 was lower in ob/ob than inWT cardiomyocytes. TRPC3 was detected in glucose transporter4 (GLUT4) immunoprecipitates. Insulin exposure resulted in atranslocation of TRPC3 to the plasma membrane in WT but notin ob/ob cardiomyocytes.

Conclusions: Insulin-resistant ob/ob cardiomyocytes showed decreasesin DAG-mediated NSCC, which were accompanied by decreased TRPC3expression and defective insulin-mediated trafficking of thisprotein.

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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