Elevated intracellular Ca²⁺/CaM bind to and activate CaMKII, CaMKK, CaMKI, and CaMKIV. CaMKII autophosphorylates to generate significant autonomous activity (see Figure 1). Primary targets of CaMKK are CaMKI (cytosolic) and CaMKIV (nuclear)—these require binding of Ca²⁺/CaM to both CaMKK and CaMKI/CaMKIV (see Figure 1). Secondary substrates of CaMKK, which are phosphorylated at much slower rates than CaMKI and CaMKIV, are PKB/Akt and members of the AMP-kinase family, including SAD-B. Crosstalk between adenylyl cyclase (A.C.)/PKA to inhibit CaMKK and between CaMKI to activate MEK/Erk are illustrated. See text for details.

(Top right) Neurotropins. Initial outgrowth of neurites to form dendrites (total length ~100 μm) is regulated in part by spontaneous and/or neurotropin-mediated (e.g., BDNF) activation of lipid-modified CaMKIγ that is colocalized in a lipid raft with Rac and its GEF, STEF. This signaling pathway is postulated to enhance actin polymerization and thereby promote dendrite formation. Neuronal Activity. Continued dendritic arborization (total length >1000 μm) via neuronal activity requires Ca²⁺ influx through the NMDAR to activate CaMKK and both α and γ CaMKI. The CaMKIγ activates the MEK/Erk pathway to stimulate CREB-dependent synthesis of Wnt-2 and microRNA132 (miR132). Wnts are known to stimulate dendritic development via β-catenins, and miR132 suppresses translation of p250GAP, thereby stimulating Rac1 and dendritic outgrowth. Downstream targets of CaMKIα in this system remain to be identified—potential candidates are discussed in the text (Neuronal Development and Table 1). Modified figure used by permission (Ciani and Salinas, 2008).

(A) CaM-kinase domains: catalytic domains, green; autoinhibitory domains, orange; Ca²⁺/CaM-binding domains, yellow; association domain (CaMKII), red. (Reproduced by permission from Soderling and Stull, 2001).
(B) Effects of Ca²⁺/CaM and autophosphorylation and/or phosphorylation on total kinase activity (+Ca²⁺/CaM, blue) or autonomous activity (−Ca²⁺/CaM, gray). The putative autophosphorylation site (S/T?) in CaMKIV is unknown. See text for details (Structure and Regulatory Mechanisms).

Neuronal activity, via Ca²⁺ influx through the NMDAR, can activate both CaMKII and CaMKK/CaMKI. (Left side) CaMKII is complexed with PSD-95 and the Rac GEF kalarin-7, which it phosphorylates and activates to promote Pak-mediated actin formation and dendritic spines. (Right side) Similarly, CaMKK and CaMKIα are part of a multiprotein complex with the Rac GEF βPIX and GIT1, which localizes it in spines. CaMKI phosphorylates and activates βPIX to stimulate Rac- and Pak-mediated spine and synapse formation.

(Top) Hippocampal CA1 LTP induction elicits an NMDAR-mediated spike of [Ca²⁺]_I in dendritic spines. This elevated Ca²⁺/CaM triggers rapid CaMKII activation (KII act) and intramolecular autophosphorylation (KII~P) to generate autonomous CaMKII activity that persists, even after slow dissociation of Ca²⁺/CaM, for at least 1 hr. This autonomous CaMKII activity can phosphorylate numerous substrates in the postsynaptic density that may contribute to synaptic potentiation. The elevated spine Ca²⁺/CaM also activates CaMKK to phosphorylate (KI~P) and activate CaMKI (KI act). Although CaMKI phosphorylation persists for at least 1 hr, its activity is more transient since autonomous activity is not generated (see Figure 1). However, even when [Ca²⁺]_I returns to basal values, CaMKI will remain somewhat activated by basal Ca²⁺/CaM due to its activity via CaMKK phosphorylation. If the LTP induction protocol results in CaMKI-mediated transient incorporation of Ca²⁺-permeable AMPARs, the [Ca²⁺]_I should remain somewhat elevated for ~20–25 min due to spontaneous activation of the AMPARs (data not shown). This source of [Ca²⁺]_I may uniquely activated Ca²⁺-dependent proteins necessary for maintenance of the LTP. (Bottom) LTP induction also promotes a transient (3–10 min) phosphorylation (KIV~P) and activation (KIV act) of CaMKIV in the nucleus that is thought to promote CREB-dependent gene transcription that may be necessary for maintenance of LTP. See section on Synaptic Plasticity for details.