Figure 1. The Ca²⁺/CaM-dependent kinase cascade mediates pleiotropic metabolic responses to physiologic and pathophysiologic stimuli.

Upstream extracellular signals such as insulin from the pancreas, adipogenic stimuli from white adipose tissue (WAT), and lipopolysaccharide (LPS), amino acids, hormones and glucose from the circulation bind to their respective receptors that trigger a rise in intracellular Ca²⁺ concentration and accumulation of Ca²⁺/CaM targets such as CaMKK2. The increased affinity and binding of Ca²⁺/CaM for CaMKK2 results in an increase in CaMKK2 kinase activity, which phosphorylates and activates CaMKIV, AMPK and CaMKI. Activation of CaMKI is involved in regulation of cell growth, as observed in neurite elongation and branching [73] as well as during cell cycle control [74]. CaMKK2-dependent activation of AMPK leads to regulation of energy balance, particularly in the brain [10], liver [33] and adipose [44]. Regulation of CaMKIV activity results in control of protein synthesis and gene expression programs responsive to nutrients [35] and hormones [14].