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Vol. 287, Issue 2, 733-743, November 1998
Department of Pharmacology and Center for Molecular Neuroscience,
Vanderbilt University School of Medicine, Nashville, Tennessee (S.A.,
A.G., L.J.D., R.D.B.) and
Department of Anatomy and Cell Biology, Emory
University School of Medicine, Atlanta, Georgia (H.C.H.)
Using SK-N-SH cells, we observe that muscarinic acetylcholine receptor
activation by methacholine (MCh) rapidly and selectively diminishes
l-NE transport capacity (Vmax) with little or no change in
norepinephrine (NE) Km and without apparent
effects on membrane potential monitored directly under current clamp.
Over the same time frame, MCh exposure reduces the density of
[3H]nisoxetine binding sites (Bmax) in intact cells but
not in total membrane fractions, consistent with a loss of transport
capacity mediated by sequestration of transporters rather than changes in intrinsic transport activity or protein degradation. Similar changes
in NE transport and [3H]nisoxetine binding capacity are
observed after phorbol ester (
-PMA) treatment. Inhibition of PKC by
antagonists and downregulation of PKC by chronic treatment with phorbol
esters abolishes -PMA-mediated effects but produce only a partial
blockade of MCh-induced effects. Neither muscarinic acetylcholine
receptor nor PKC activation require extracellular Ca++ to
diminish NET activity. In contrast, treatment of cells with the
Ca++/ATPase antagonist, thapsigargin in
Ca++-free medium, eliminates the staurosporine-insensitive
component of MCh regulation. These findings were further corroborated
by the ability of
[1,2-bis(o-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid
tetra(acetoxymethyl)ester application in Ca++-free medium
to abolish NET regulation by MCh. Although they may contribute to basal
NET expression, we could not implicate CaMKII-, PKA- or nitric
oxide-linked pathways in MCh regulation. Together, these findings
1) provide evidence in support of G-protein coupled receptor-mediated regulation of catecholamine transport, 2) reveal intracellular Ca++-sensitive, PKC-dependent and
-independent pathways that serve to regulate NET expression and 3)
indicate that the diminished capacity for NE transport evident after
mAChR and PKC activation involves a redistribution of NET protein.
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