The Ca(2+)/Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft

Abstract

Calcium (Ca(2+)) 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 Ca(2+)/CaM is the activation of a highly conserved Ca(2+)/CaM kinase (CaMK) cascade that amplifies Ca(2+) signals through a series of subsequent phosphorylation events. Proper regulation of Ca(2+) flux is necessary for whole-body metabolism and disruption of Ca(2+) homeostasis has been linked to various metabolic diseases. Here we provide a synthesis of recent advances that highlight the roles of the Ca(2+)/CaMK axis in key metabolic tissues. An appreciation of this information is critical to understanding the mechanisms by which Ca(2+)/CaM-dependent signaling contributes to metabolic homeostasis and disease.

Keywords: AMPK; CaMKIV; CaMKK2; calcium; calmodulin.

Figure I, Box 2. Timeline of CaM- and CaMK-related publications

Graphic representation of the historical increase in the number of PubMed® publications on CaM (black line) and the Ca²⁺/CaM-dependent kinases (CaMK) (red line). Discoveries highlighted include cloning of the genes for the following cascade components: CaM - 1981 [65]; smooth muscle myosin light chain kinase (smMLCK) - 1986 [66]; CaM kinase II α (CaMKIIα) - 1987 [67]; CaMKIV - 1991 [68]; CaMKI - 1993 [69]; AMP-activated protein kinase α (AMPKα) - 1995 [72]; CaMK kinase 1 (CaMKK1) - 1995 [70]; CaMKK2 - 1997 [71].

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].

Figure 2. CaMKK2 regulates whole body energy homeostasis through coordinating the actions of key metabolic tissues

In the brain, CaMKK2 and AMPK function to control appetite and energy homeostasis [10], whereas CaMKK2-mediated activation of CaMKIV is required for cerebellar granule cell development [29]. CaMKK2 is required for regulation of sympathetic tone [14] and long-term memory formation [19,23], and is implicated in anxiety and bipolar disorder [75,76]. Within the liver, CaMKK2 regulates AMPK to promote gluconeogenesis while suppressing de novo lipogenesis [33]. The CaMKK2/CaMKIV axis in the liver also contributes to non-alcoholic fatty liver disease (NAFLD) and is instrumental during progression of hepatocellular carcinoma [35]. In white adipose tissue (WAT), CaMKK2 phosphorylates AMPK to regulate adiposity and pre-adipocyte differentiation [44]. In brown adipose tissue (BAT), CaMKK2 plays a role in adaptive thermogenesis. In the pancreas, CaMKK2 acts as a gatekeeper for β-cell insulin secretion and controls peripheral insulin sensitivity [52]. Within the cardiovascular system, CaMKK2 confers protection against atherosclerosis [30]. In bone, CaMKK2 also functions to regulate bone mass accrual [14,16].

Figure 3. Liver-centric metabolic functions of CaMKK2

In the liver, ablation of CaMKK2 impacts the metabolic flexibility of numerous pathways as indicated by the asterisks (*). Loss of CaMKK2 in response to high fat diet feeding reduces levels of free fatty acids (FFAs), triglyercides (TGs) and very low-density lipoproteins (VLDL) as well as low densitiy lipoproteins and cholesterol (not depicted) [52]. Consistent with these observations, hepatic-specific ablation of CaMKK2 is sufficient to confer improved insulin sensitivity [33]. Primary hepatocytes devoid of CaMKK2 show increased de novo lipogenesis along with increased β-oxidation [33]. In the context of hepatic cancer, CaMKK2 is essential for driving mTOR/S6K signaling to promote protein synthesis that increases cancer cell proliferation [35].