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Vol. 299, Issue 2, 666-677, November 2001
Department of Pharmacology and Center for Molecular Neuroscience,
Vanderbilt University School of Medicine, Nashville, Tennessee
Presynaptic, cocaine- and antidepressant-sensitive norepinephrine (NE)
transporters (NETs) dictate levels of extracellular NE after vesicular
release. Recent studies suggest that G protein-coupled receptors linked
to protein kinase C (PKC) down-regulate cell surface NET protein levels
and diminish NE uptake capacity. We identified distinct
phosphatidylinositol 3-OH kinase (PI3K)-linked pathways supporting
basal and insulin-triggered NE transport in the human noradrenergic
neuroblastoma, SK-N-SH. Acute (0-60 min) insulin treatments produced a
time- and concentration-dependent stimulation of NE transport, resolved
in kinetic studies as an enhancement of NE transport capacity
(Vmax) without an alteration in NE
Km. Basal and insulin-modulated NET
activities were reduced by the tyrosine kinase inhibitor genistein and
the PI3K inhibitors wortmannin and LY-294002, but not by the PKC
inhibitor staurosporine. PI3K activation was found to support
phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK).
However, basal and insulin-stimulated NET activities were
differentiated by their reliance on p38 MAPK activation. Thus, the p38
MAPK inhibitor SB203580 and SB202190 abolished insulin activation of NE
transport yet failed to impact basal NET activity. Moreover, p38 MAPK
activation and insulin activation of NETs were found to be sensitive to
external Ca2+ depletion, blockade of voltage-sensitive
Ca2+ channels, and inhibition of protein phosphatase 2A.
Effects of tyrosine kinase and PI3K inhibitors on basal NET uptake
appear to arise from a loss of cell surface NET protein, whereas the p38 MAPK-dependent enhancement of NE transport occurs without a
detectable enhancement of surface NET. Our findings establish two
distinct pathways for regulation of NE uptake involving PI3K, one
linked to transporter trafficking and a second linked to
Ca2+-dependent, p38 MAPK phosphorylation that promotes
activation of cell surface NETs.
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