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A Novel, Voltage-Dependent Nonselective Cation Current Activated by Insulin in Guinea Pig Isolated Ventricular Myocytes

From the Department of Physiology & Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, UK. Present affiliation for Dr Zhang is Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Correspondence to Dr Jules Hancox, Department of Physiology & Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK. E-mail jules.Hancox{at}bristol.ac.uk

Insulin regulates cardiac metabolism and function by targeting metabolic proteins or voltage-gated ion channels. This study provides evidence for a novel, voltage-dependent, nonselective cation channel (NSCC) in the heart. Under voltage clamp at 37°C and with major known conductances blocked, insulin (1 nmol/L to 1 µmol/L) activated an outwardly rectifying current (I_insulin) in guinea pig ventricular myocytes. I_insulin could be carried by Cs⁺, K⁺, Li⁺, and Na⁺ ions but not by NMDG⁺. It was inhibited by the NSCC blockers gadolinium and SKF96365 but not flufenamic acid. I_insulin was largely blocked by the insulin receptor tyrosine kinase inhibitor HNMPA-(AM)₃ and by the phospholipase C inhibitor U73122 but not by its inactive analogue U73433. Staurosporine, a potent blocker of protein kinase C, did not prevent the activation of I_insulin. Application of an analogue of diacylglycerol, 1-oleoyl-2-acetyl-sn-glycerol, mimicked the effect of insulin. This activated an outwardly rectifying NSCC that could be carried by Cs⁺, K⁺, Li⁺, or Na⁺ and that was blocked by gadolinium but not by flufenamic acid or staurosporine. We conclude that the intracellular pathway leading to activation of this novel cardiac NSCC involves phospholipase C, is protein kinase C–independent, and may depend on direct channel activation by diacylglycerol.

Key Words: cardiac myocytes • diacylglycerol • insulin • nonselective cation current

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