Figure 2.

CaMKKβ/2 activation mechanism and immunohistochemical localization in the rat brain. (A) Sagittal section of the adult rat brain immunostained with a monoclonal antibody against CaMKKβ/2 (reproduced from Ref. [61], with permission from John Wiley and Sons). CA1 and CA3, CA1 and CA3 subregions of Ammon’s horn of the hippocampus; Cb, cerebellar cortex; CP, caudate putamen; Cx, cerebral cortex; DG, dentate gyrus; MO, medulla oblongata; OB, olfactory bulb; Pn, pontine nuclei; SNr, substantia nigra pars reticulata; Th, thalamus; and Tu, olfactory tubercle. Scale bar = 2.5 mm. (B) Proposed model of activation mechanism of CaMKKβ/2. CaMKKβ/2 is constitutively active, exhibiting Ca²⁺/CaM-independent activity (60–70% of total activity), attributable to the N-terminal regulatory segment (residues 129–151, C) [22,31]. CaMKKβ/2 exhibits increased autonomous activity, caused, at least in part, by intramolecular autophosphorylation at Thr482, resulting in partial disruption of the autoinhibitory mechanism [76]. Phosphorylation at multiple sites in CaMKKβ/2 by CDK5 and GSK3 [77], activated AMPK [78] or PKA [79], likely disrupting the N-terminal regulatory function to generate autonomous activity, thereby holding the inactive kinase in the absence of Ca²⁺/CaM, in agreement with the finding that CaMKKβ/2-AMPK pathway activation requires Ca²⁺/CaM signaling [33,34,35]. (C) Amino acid sequence alignment of the N-terminal regulatory segment in rat and human CaMKKβ/2. CDK5/GSK3 phosphorylate human CaMKKβ/2 at Ser129, Ser133, and Ser137 [77]. Activated AMPK and PKA phosphorylate Thr144 in rat CaMKKβ/2 [78,79]. Modified from Ref. [68].