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1 Programme in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada
2 Programme in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
* To whom correspondence should be addressed. E-mail: amira{at}sickkids.ca.
Contracting skeletal muscle increases glucose uptake to sustain energy demand. This is achieved through a gain in glucose transporter-4 (GLUT4) at the membrane, but the traffic mechanisms and regulatory signals involved are unknown. Muscle contraction is elicited by membrane depolarization followed by a rise in cytosolic Ca2+ and actomyosin activation, drawing on ATP stores. It is unknown whether one or more of these events trigger the rise in surface GLUT4. Here we investigate the effect of membrane depolarization on GLUT4 cycling using GLUT4myc-expressing L6 myotubes devoid of sarcomeres and thus unable to contract. K+-induced membrane depolarization elevated surface GLUT4myc and this effect was additive to that of insulin, was not prevented by inhibiting phosphatidylinositol 3-kinase or actin polymerization, and did not involve Akt activation. Instead, depolarization elevated cytosolic Ca2+, and the surface GLUT4myc elevation was prevented by dantrolene (an inhibitor of Ca2+ release from sarcoplasmic reticulum) and by extracellular Ca2+ chelation. Ca2+-calmodulin-dependent protein kinase-II (CaMKII) was not phosphorylated after 10 min of K+ depolarization and the CaMK inhibitor KN62 did not prevent the gain in surface GLUT4myc. Interestingly, although 5'-AMP-activated protein kinase (AMPK) was phosphorylated upon depolarization, lowering AMPK
via siRNA did not alter the surface GLUT4myc gain. Conversely, the latter response was abolished by the protein kinase C (PKC) inhibitors bisindolylmaleimide I and calphostin C. Unlike insulin, K+ depolarization caused only a small increase in GLUT4myc exocytosis and a major reduction in its endocytosis. We propose that K+ depolarization reduces GLUT4 internalization, through signals and mechanisms distinct from those engaged by insulin. Such pathway(s) is largely independent of PI3K, Akt, AMPK and CaMKII, but may involve PKC.
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