A MECHANISM FOR SYNAPTIC FREQUENCY DETECTION THROUGH AUTOPHOSPHORYLATION OF CAM KINASE-II

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.