PubMed Journals: J Biol Chem
Source: PMID: 10187789
⇦ ⇨ J Biol Chem. 1999 Apr 9;274(15):10086-93.
Inhibition of the Ca2+/calmodulin-dependent
protein kinase I cascade by cAMP-dependent
Matsushita M(1), Nairn AC.
(1) Laboratory of Molecular and Cellular
Neuroscience, The Rockefeller University,
New York, New York 10021, USA.
Several recent studies have shown that
Ca2+/calmodulin-dependent protein kinase
I (CaMKI) is phosphorylated and activated
by a protein kinase (CaMKK) that is itself
subject to regulation by Ca2+/calmodulin.
In the present study, we demonstrate that
this enzyme cascade is regulated by cAMP-mediated
activation of cAMP-dependent protein kinase
(PKA). In vitro, CaMKK is phosphorylated
by PKA and this is associated with inhibition
of enzyme activity. The major site of
phosphorylation is threonine 108, although
additional sites are phosphorylated with
lower efficiency. In vitro, CaMKK is also
phosphorylated by CaMKI at the same sites
as PKA, suggesting that this regulatory
phosphorylation might play a role as a
negative-feedback mechanism. In intact PC12
cells, activation of PKA with forskolin
resulted in a rapid inhibition of both CaMKK
and CaMKI activity. In hippocampal slices
CaMKK was phosphorylated under basal conditions,
and activation of PKA led to an increase
in phosphorylation. Two-dimensional phosphopeptide
mapping indicated that activation of PKA
led to increased phosphorylation of multiple
sites including threonine 108. These results
indicate that in vitro and in intact cells
the CaMKK/CaMKI cascade is subject to inhibition
by PKA-mediated phosphorylation of CaMKK.
The phosphorylation and inhibition of CaMKK
by PKA is likely to be involved in modulating
the balance between cAMP- and Ca2+-dependent
signal transduction pathways.
PMID: 10187789 [Indexed for MEDLINE]