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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
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Ca2+-dependent Dephosphorylation of Kinesin Heavy Chain on beta -Granules in Pancreatic beta -Cells
IMPLICATIONS FOR REGULATED beta -GRANULE TRANSPORT AND INSULIN EXOCYTOSIS*

Matthew J. DonelanDagger , Gerardo Morfini§, Richard JulyanDagger , Scott SommersDagger , Lori HaysDagger , Hiroshi KajioDagger , Isabelle BriaudDagger , Richard A. Easom, Jeffery D. Molkentin||, Scott T. Brady§, and Christopher J. RhodesDagger **

From the Dagger  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 beta -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 beta -granules. The effect of elevated [Ca2+]i on phosphorylation of isolated beta -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 beta -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 beta  (PP2Bbeta ) 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 beta -granules from the storage pool to replenish the readily releasable pool of beta -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 beta -granule transport in beta -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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