A. Dosemeci et Rw. Albers, A MECHANISM FOR SYNAPTIC FREQUENCY DETECTION THROUGH AUTOPHOSPHORYLATION OF CAM KINASE-II, Biophysical journal, 70(6), 1996, pp. 2493-2501
A model for the regulation of CaM kinase II is presented based on the
following reported properties of the molecule: 1) the holoenzyme is co
mposed of 8-12 subunits, each with the same set of autophosphorylation
sites; 2) autophosphorylation at one group of sites (A sites) require
s the presence of Ca2+ and causes a subunit to remain active following
the removal of Ca2+; 3) autophosphorylation at another group of sites
(B sites) occurs only after the removal of Ca2+ but requires prior ph
osphorylation of a threshold number of A sites within the holoenzyme.
Because B-site phosphorylation inhibits Ca2+/calmodulin binding, we pr
opose that, for a given subunit, phosphorylation of a B site before an
A site prevents subsequent phosphorylation at the A site and thereby
locks that subunit in an inactive state. The model predicts that a thr
eshold activation by Ca2+ will initiate an ''autophosphorylation phase
.'' Once started, intra-holoenzyme autophosphorylation will proceed, o
n A sites during periods of high [Ca2+] and on B sites during periods
of low [Ca2+]. At ''saturation,'' that is when every subunit has been
phosphorylated on a B site, the number of phosphorylated A sites and,
therefore, the kinase activity will reflect the relative durations of
periods of high [Ca2+] to periods of low [Ca2+] that occurred during t
he autophosphorylation phase. Using a computer program designed to sim
ulate the above mechanism, we show that the ultimate state of phosphor
ylation of an array of CaM kinase II molecules could be sensitive to t
he temporal pattern of Ca2+ pulses. We speculate that such a mechanism
may allow arrays of CaM kinase II molecules in postsynaptic densities
to act as synaptic frequency detectors involved in setting the direct
ion and level of synaptic modification.