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(Circulation Research. 2006;98:1390.)
© 2006 American Heart Association, Inc.

Cellular Biology

Insulin-Like Growth Factor-1 and PTEN Deletion Enhance Cardiac L-Type Ca²⁺ Currents via Increased PI3K/PKB Signaling

Hui Sun, Benoit-Gilles Kerfant^*, Dongling Zhao^*, Maria G. Trivieri, Gavin Y. Oudit, Josef M. Penninger, Peter H. Backx

From the Departments of Physiology and Medicine (H.S., B.G.-K., D.Z., M.G.T., G.Y.O., P.H.B.), Division of Cardiology (M.G.T., G.Y.O., P.H.B.), University Health Network, and Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research (P.H.B.), University of Toronto, Canada; and Institute for Molecular Biotechnology (J.M.P.), Austrian Academy of Science, Vienna.

Correspondence to Dr Peter Backx, Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research, Fitzgerald Bldg, Rm 68, 150 College St, Toronto, Ontario M5S 3E2, Canada. E-mail p.backx{at}utoronto.ca

Ca²⁺ influx through the L-type Ca²⁺ channel (I_Ca,L) is a key determinant of cardiac contractility and is modulated by multiple signaling pathways. Because the regulation of I_Ca,L by phosphoinositide-3-kinases (PI3Ks) and phosphoinositide-3-phosphatase (PTEN) is unknown, despite their involvement in the regulation of myocardial growth and contractility, I_Ca,L was recorded in myocytes isolated from mice overexpressing a dominant-negative p110 mutant (DN-p110) in the heart, lacking the PI3K gene (PI3K^–/–) or with muscle-specific ablation of PTEN (PTEN^–/–). Combinations of these genetically altered mice were also examined. Although there were no differences in the expression level of Ca_V1.2 proteins, basal I_Ca,L densities were larger (P<0.01) in PTEN^–/– myocytes compared with littermate controls, PI3K^–/–, or DN-p110 myocytes and showed negative shifts in voltage dependence of current activation. The I_Ca,L differences seen in PTEN^–/– mice were eliminated by pharmacological inhibition of either PI3Ks or protein kinase B (PKB) as well as in PTEN^–/–/DN-p110 double mutant mice but not in PTEN^–/–/PI3K^–/– mice. On the other hand, application of insulin-like growth factor-1 (IGF-1), an activator of PKB, increased I_Ca,L in control and PI3K^–/–, while having no effects on I_Ca,L in DN-p110 or PTEN^–/– mice. The I_Ca,L increases induced by IGF-1 were abolished by PKB inhibition. Our results demonstrate that IGF-1 treatment or inactivation of PTEN enhances I_Ca,L via PI3K-dependent increase in PKB activation.

Key Words: PI3K • isoforms • PTEN • Akt/PKB • L-type Ca²⁺ channels

Related Article:

Mission Impossible: IGF-1 and PTEN Specifically "Akt"ing on Cardiac L-Type Ca²⁺ Channels

Timothy J. Kamp and Nipavan Chiamvimonvat
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