A novel action of insulin on cardiac membrane.

Insulin is an essential hormone for the control of blood glucose level and glucose metabolism. Additionally, insulin mediates a wide spectrum of biological responses including lipid metabolism, protein synthesis, activation of transcription of specific genes, modulation of cellular growth and differentiation, and functional regulation of ion channels and transporters in various types of cells. The action of insulin is mediated through the insulin receptor, a transmembrane glycoprotein with intrinsic protein tyrosine kinase activity. The insulin receptor is an 2/ 2 tetramer with the -subunit located on the extracellular face of the plasma membrane having the insulin binding site. The intracellular portion of the -subunit contains the insulin-regulated tyrosine protein kinase. Insulin action is exerted through its binding to the -subunit of the insulin receptor, resulting in regulation of the tyrosine protein kinase located in the -subunit of the insulin receptor. This leads to the autophosphorylation of the receptor and other substrates including insulin receptor substrate-1 (IRS-1) and other related proteins. Diverse and complex intracellular signaling pathways downstream to the receptor activation are involved in different responses depending on the target proteins, and it is believed that intrinsic tyrosine kinase is critical for the signal transduction of insulin action.1,2 Insulin receptors are also present in cardiac membranes. Because tissue sensitivity to insulin is dictated by receptor abundance, it is relevant to note that the number of functional insulin receptors in the heart is comparable to that in other insulin-sensitive cell types (10 000 to 100 000 per cell).3 In the heart, insulin regulates various physiological and pathophysiological functions, including myocardial energy metabolism, contractility, protein expression, hypertrophy and cardiomyopathy in diabetes mellitus, and ion transport mechanisms.3 The actions of insulin on ionic channels and transporters of normal cardiac membrane have been considered to be unremarkable,4 but recent evidence has been accumulating to indicate the regulatory roles played by insulin on various channels and transporters, eg, stimulation of the L-type Ca current5,6 and the Na -Ca exchanger,7 and upregulation of K channels.8 Given that some of these results were obtained at unphysiologically high insulin levels, the actual contribution of each process to physiological function and signal transduction pathways needs careful consideration. In the study reported in this issue of Circulation Research,9 Zhang and Hancox demonstrated that insulin at 1 nanomol to 1 mol concentrations activated a novel voltage-dependent nonselective cation current (NSCC) in guinea pig ventricular myocytes, under conditions where other conductances were inhibited. The NSCCs so far reported in cardiac membrane are intracellular Ca -activated and background type,10,11 and stretch-activated channels,12 which are voltage-independent with a linear I-V relation. Zhang and Hancox found that the ion selectivity of this current was equally permeable to Cs , K , Li , and Na , but not to NMDG. As to the pharmacological sensitivity, insulin-activated current (Iinsulin) was blocked by NSCC blockers, Gd and SKF96365, but not by flufenamic acid (FFA), exhibiting some but not complete similarity to NSCC in other cell types.13–15 Activation of Iinsulin was abolished by pretreatment with insulin-receptor tyrosine kinase inhibitor, hydroxy-2-naphthalenyl-methyl phosphonic acid trisacetoxy-methyl ester (HNMPA(AM)3). This study, therefore, appears to be the first report describing the involvement of tyrosine kinase phosphorylation in the activation of cardiac NSCC. A specific phospholipase C (PLC) inhibitor (U73122) significantly abbreviated the current activation, whereas an inactive analogue (U73433) did not affect the response, suggesting that a PLC-dependent pathway is involved in the current activation. Their data also suggest that the insulin-induced activation of NSCC is possibly mediated by a direct involvement by diacylglycerol (DAG) but not by activation of protein kinase C (PKC). This interpretation was based on their observations that membrane-permeable DAG analogue, 1-oleoyl-2-acetyl-sn-glycerol (OAG), mimicked the effect of insulin, but application of staurosporine to inhibit PKC did not affect the response. Therefore, the study contains two novel findings: insulin activates voltage-dependent NSCC in cardiac cells, and the type of NSCC appears to represent a ligand-gated channel directly activated by DAG. This short report may shed light on a novel and important action of insulin on cardiac cell physiology and its function in several aspects. The insulin-activated NSCC carries cationic current flows, including Na , in an outward-going rectification at positive voltages and inward direction at negative voltages. This current flow may, in turn, influence the activity of the Na -Ca exchanger inducing increased Ca influx into myocardial cells. This can explain, at least in part, the increased contractility produced by insulin in the heart. The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. Correspondence to Masayasu Hiraoka, MD, PhD, Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. E-mail [email protected] (Circ Res. 2003;92:707-709.) © 2003 American Heart Association, Inc.