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Originally published In Press as doi:10.1074/jbc.M203345200 on April 26, 2002
J. Biol. Chem., Vol. 277, Issue 27, 24232-24242, July 5, 2002
Ca2+-dependent Dephosphorylation of
Kinesin Heavy Chain on -Granules in Pancreatic -Cells
IMPLICATIONS FOR REGULATED -GRANULE TRANSPORT AND INSULIN
EXOCYTOSIS*
Matthew J.
Donelan ,
Gerardo
Morfini§,
Richard
Julyan ,
Scott
Sommers ,
Lori
Hays ,
Hiroshi
Kajio ,
Isabelle
Briaud ,
Richard A.
Easom¶,
Jeffery D.
Molkentin ,
Scott T.
Brady§, and
Christopher J.
Rhodes **
From the Pacific Northwest Research Institute and
Department of Pharmacology, University of Washington, Seattle,
Washington 98112, the § Department of Cell Biology,
University of Texas Southwestern Medical Center, Dallas, Texas 75390, the ¶ Department of Molecular Biology & Immunology, University of
North Texas Health Science Center, Fort Worth, Texas 76107, and the
Division of Molecular Cardiovascular Biology, Children's
Hospital Medical Center, Cincinnati, Ohio 45229
The specific biochemical steps required
for glucose-regulated insulin exocytosis from -cells are not well
defined. Elevation of glucose leads to increases in cytosolic
[Ca2+]i and biphasic
release of insulin from both a readily releasable and a storage pool of
-granules. The effect of elevated [Ca2+]i on phosphorylation of
isolated -granule membrane proteins was evaluated, and the
phosphorylation of four proteins was found to be altered by
[Ca2+]i. One (a 18/20-kDa
doublet) was a Ca2+-dependent increase in
phosphorylation, and, surprisingly, three others (138, 42, and 36 kDa)
were Ca2+-dependent dephosphorylations. The
138-kDa -granule phosphoprotein was found to be kinesin heavy chain
(KHC). At low levels of [Ca2+]i
KHC was phosphorylated by casein kinase 2, but KHC was rapidly
dephosphorylated by protein phosphatase 2B (PP2B ) as
[Ca2+]i increased. Inhibitors
of PP2B specifically reduced the second,
microtubule-dependent, phase of insulin secretion, suggesting that dephosphorylation of KHC was required for transport of
-granules from the storage pool to replenish the readily releasable pool of -granules. This is distinct from synaptic vesicle
exocytosis, because neurotransmitter release from synaptosomes did not
require a Ca2+-dependent KHC dephosphorylation.
These results suggest a novel mechanism for regulating KHC function and
-granule transport in -cells that is mediated by casein kinase 2 and PP2B. They also implicate a novel regulatory role for
PP2B/calcineurin in the control of insulin secretion downstream of a
rise in [Ca2+]i.
*
This work was supported by National Institutes of Health
Grant DK47919 (to C. J. R.) and Grants NS23868, NS23320,
NS41170, and AG12646 (all to S. T. B.); by NASA Grant
NAG2-962 (to S. T. B.); by a Juvenile Diabetes Foundation
grant (to S. T. B.); and by Welch Foundation Grant 1237 (to
S. T. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
**
To whom correspondence should be addressed: Pacific Northwest
Research Inst., 720 Broadway, Seattle, WA 98112. Tel.:
206-860-6777; Fax: 206-726-1202; E-mail: cjr@pnri.org.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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