The Ca2+/Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft

Calcium (Ca2+) is an essential ligand that binds its primary intracellular receptor calmodulin (CaM) to trigger a variety of downstream processes and pathways. Central to the actions of Ca2+/CaM is the activation of a highly conserved Ca2+/CaM kinase (CaMK) cascade that amplifies Ca2+ signals through a series of subsequent phosphorylation events. Proper regulation of Ca2+ flux is necessary for whole-body metabolism and disruption of Ca2+ homeostasis has been linked to various metabolic diseases. Here we provide a synthesis of recent advances that highlight the roles of the Ca2+/CaMK axis in key metabolic tissues. An appreciation of this information is critical to understanding the mechanisms by which Ca2+/CaM-dependent signaling contributes to metabolic homeostasis and disease.