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J Biol Chem, Vol. 274, Issue 7, 4027-4035, February 12, 1999
, and
From the Departments of Physiology and of
Munc18a, a mammalian neuronal homologue of
Saccharomyces cerevisiae Sec1p protein, is essential for
secretion, likely as a result of its high affinity interaction with the
target SNARE protein syntaxin 1a (where SNARE is derived from SNAP
receptor (the soluble N-ethylmaleimide-sensitive fusion
protein)). However, this interaction inhibits vesicle SNARE
interactions with syntaxin that are required for secretory vesicles to
achieve competency for membrane fusion. As such, regulation of the
interaction between Munc18a and syntaxin 1a may provide an important
mechanism controlling secretory responsiveness.
Cyclin-dependent kinase 5 (Cdk5), a member of the Cdc2
family of cell division kinases, co-purifies with Munc18a from rat
brain, interacts directly with Munc18a in vitro, and
utilizes Munc18a as a substrate for phosphorylation. We have now
demonstrated that Cdk5 is capable of phosphorylating Munc18a
in vitro within a preformed Munc18a·syntaxin 1a
heterodimer complex and that this results in the disassembly of the
complex. Using site-directed mutagenesis, the Cdk5 phosphorylation site on Munc18a was identified as Thr574. Stimulation of
secretion from neuroendocrine cells produced a corresponding rapid
translocation of cytosolic Cdk5 to a particulate fraction and an
increase of Cdk5 kinase activity. Inhibition of Cdk5 with olomoucine
decreased evoked norepinephrine secretion from chromaffin cells, an
effect not observed with the inactive analogue iso-olomoucine. The
effects of olomoucine were independent of calcium influx as evidenced
by secretory inhibition in permeabilized chromaffin cells and in cells
under whole-cell voltage clamp. Furthermore, transfection and
expression in chromaffin cells of a neural specific Cdk5 activator,
p25, led to a strong increase in nicotinic agonist-induced secretory
responses. Our data suggest a model whereby Cdk5 acts to regulate
Munc18a interaction with syntaxin 1a and thereby modulates the level of
vesicle SNARE interaction with syntaxin 1a and secretory responsiveness.
Pharmacology, University of Michigan,
Ann Arbor, Michigan 48109
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