Diagrams comparing the effects of weak and strong calcium entry on kinase activity. After activity-induced elevation of cytosolic Ca2+, Ca2+/CaM-dependent autophosphorylation of CaMKII is accelerated to a degree that depends on the size, location, and timing of the elevation, but CaMKII dephosphorylation is also promoted by the stimulatory effect of Ca2+/CaM-dependent PP2B (calcineurin), acting indirectly through the PP2B-dependent repressor protein Inhibitor 1, on PP1. [PP2A is also phosphorylated and activated by a Ca2+-dependent kinase, but, in this case, the kinase is casein kinase 2α (Heriche et al., 1997).] When Ca2+ entry is submaximal (top), the activity of PP1, together with basal PP2A activity, establishes a steady-state level of active CaMKII that is relatively low. In addition, the stimulus is too weak to significantly activate PKA. Weak Ca2+ entry also stimulates some mitochondrial O2- production, but the amount is small enough that it is rapidly degraded by SOD. Red lettering indicates enhanced activity; solid arrows, stimulatory effects; dashed arrows, inhibitory effects. Line weights correlate with relative strength; crossed arrows indicate blocking effects. After strong Ca2+ entry (bottom), CaMKII is upregulated because mitochondria in high-Ca2+ microdomains close to subplasmalemmal sites of Ca2+ entry accumulate large amounts of Ca2+ and increase their production of O2-, which in turn deactivates PP2B and PP2A and suppresses the dephosphorylation of CaMKII. This leads to an elevated steady-state level of phosphorylated CaMKII. Similar O2--modulated, phosphatase-dependent mechanisms upregulate PKA, which in addition further elevates CaMKII because the suppressor protein Inhibitor 1, which blocks PP1 and therefore CaMKII deactivation, is phosphorylated (activated) by PKA (Soderling and Derkach, 2000). In contrast to CaMKII and PKA, pPKCα translocation and subsequent upregulation does not depend on phosphatase activity. The mechanism by which O2- contributes to Ca2+-mediated pPKCα activation is not known, but one possibility envisions direct modulation by mitochondrial O2--induced thiol oxidation (Knapp and Klann, 2000). DAG, Diacylglycerol; ER, endoplasmic reticulum; PLC, phospholipase C.