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Mol Endocrinol. Dec 2008; 22(12): 2759–2765.
Published online Oct 9, 2008. doi:  10.1210/me.2008-0312
PMCID: PMC2626202

Commentary: The Year in Basic Science: Calmodulin Kinase Cascades

Abstract

This article highlights studies published during the past year that represent significant scientific achievements in the world of calmodulin kinase cascades. Calmodulin is the primary receptor for calcium present in all cells. The binding of its calcium ligand results in a conformational change in calmodulin, which allows the calcium-calmodulin complex to interact with many different targets. In the studies to be summarized in this review, the particular calmodulin cascade involved is shown to be the pathway responsible for important biological responses, including long-term memory formation, dendritic cell survival, hypercapnia, neuronal migration, synapse formation, autophagy, fatty acid oxidation, and energy balance. In some cases, the pathway was previously unknown, and the identification of the calmodulin cascade represents the definition of roles. In other cases, manipulating the cascade has suggested therapeutic approaches to certain diseases, most significantly, type 2 diabetes and obesity.

AS PART OF The Year in Basic Science session at ENDO 2008, I presented “The Year in Calmodulin Kinase Cascades.” From a large number of suggestions by my colleagues as to what the top studies in this area in the past year had been, I narrowed their nominations down to eight by selecting those that received the most votes.

Although this is not a subject that would typically be presented at an Endocrine Society meeting, I nevertheless thought it would be relevant because of the pivotal role calcium plays in cell signaling. Calcium is the most pervasive of all second messengers because every cell uses calcium to initiate a variety of regulatory pathways that alter function. Calmodulin is the primary cellular receptor for calcium, and the interaction between calcium and calmodulin is analogous to the binding of a steroid hormone to its cognate receptor. This binding of calcium results in a conformational change in calmodulin, which allows it to interact with many different targets. The targets relevant to this discussion are some of the calmodulin kinases (CaMKs). Importantly, in each of the eight cell pathways explored here, calmodulin kinase kinase-β (CaMKKβ) facilitates formation of a signaling complex that is involved in mediating the biological response.

CaMK CASCADE BACKGROUND

The term “calmodulin kinase cascade” that has recently been reviewed (1,2) arose from its similarity to the MAPK pathway. In the MAPK pathway, three enzymes are sequentially activated and phosphorylate each other on their respective activation loops because they are linked together in close proximity via a fourth protein that functions as a scaffold. Similarly, the CaMKKs phosphorylate CaMKI and CaMKIV on a specific Thr residue, present on the activation loop of each, leading to their activation. In addition, CaMKKβ also functions as a scaffold for a signaling complex that minimally includes calmodulin, the CaMK substrate of CaMKKβ and the substrate of the CaMK. Figure 11 illustrates the CaMK cascade concept. All of the enzymes shown are expressed in high abundance in the brain. KN-93 is a small molecule inhibitor of CaMKI and CaMKIV but also inhibits calmodulin-dependent protein kinase II (CaMKII), which is ubiquitously expressed and well studied. Therefore, inhibition of a cellular process by KN-93 implies that the process involves CaMKI, CaMKIV, or CaMKII. Because the two CaMKKs (α and β) are inhibited by STO-609 and phosphorylate CaMKI and CaMKIV but not CaMKII, inhibition of a cellular process by STO-609 and KN-93 implies that the process requires a CaMKK as well as either CaMKI or CaMKIV and is thus considered to be regulated by a CaMK cascade. To identify the target of the CaMKK, it is possible to use short hairpin RNA (shRNA) or small interfering RNA (siRNA) to knock down CaMKI or CaMKIV. On the other hand, if the process is inhibited by KN-93 but not STO-609, it is probably regulated by CaMKII. Finally, if the process is inhibited by STO-609 but not KN-93, it is likely that AMP-dependent kinase (AMPK) is the downstream target of the CaMKK. This can be tested using the selective inhibitor of AMPK, compound C.

Figure 1
CaMK Cascades

Whereas CaMKI is expressed in all cells and is involved in cell proliferation, CaMKIV is expressed primarily in cells of the hematopoietic system, the gonads, and components of the central and peripheral nervous systems. CaMKKα and CaMKKβ are also expressed abundantly in the nervous system and some hematopoietic cells, but where they might otherwise be expressed is the subject of some controversy because the reagents to detect them at the protein level are not particularly robust or specific. Many studies are currently underway that attempt to identify CaMKKα or CaMKKβ as a component of a plethora of signaling cascades that are initiated by a rise in cellular calcium (2). To aid in this quest both germline and conditional knockout mice have been generated for CaMKIV, CaMKKα, and CaMKKβ, but none have been successfully produced so far for CaMKI (for which four isoforms exist and each is the product of a separate gene). Although it may seem strange to find AMP-dependent kinase in a calmodulin cascade because AMPK is not a direct calmodulin target, it is the most recent physiologically relevant substrate identified for CaMKKβ (Fig. 11).). This substrate is relevant to the studies discussed in Part II.

CaMKIV SIGNALING COMPLEX

Figure 22 illustrates the CaMKIV signaling cycle, which is the CaMK cascade the mechanism of which is best understood currently (1). In the cytoplasm, CaMKIV is in a complex that includes a CaMKK and protein phosphatase 2A (PP2A). In this complex, CaMKIV is inactive. In response to a stimulus that increases intracellular calcium, some of the calcium binds calmodulin, and the calcium-calmodulin complex binds to CaMKIV, which displaces PP2A because calcium-calmodulin and PP2A bind to the same site on CaMKIV. This binding of calcium-calmodulin not only displaces PP2A but results in a conformational change of CaMKIV, resulting in a basal level of kinase activity and exposing the activation loop for phosphorylation by the CaMKK. The CaMKK-phosphorylated from of CaMKIV is now fully active and remains so even if the calcium levels in the cell decline and calmodulin as well as CaMKK are disassociated. Therefore, this activity, which is now independent of calcium-calmodulin or CaMKK, has been termed “autonomous.” It is only the autonomous form of CaMKIV that is translocated into the nucleus by an importin α-dependent mechanism where it participates in the regulation of transcription (1). Thereafter, a particular isoform of PP2A will rebind CaMKIV in the nucleus and dephosphorylate the activation loop Thr residue. This inactivates CaMKIV and allows it to be exported from the nucleus into the cytoplasm. Whether the recycled CaMKIV is degraded or enters the cycle again is unclear because only a small fraction of total cytoplasmic CaMKIV is activated in response to a calcium transient. At any rate it is this sequence of events that constitute the CaMKIV activity cycle or cascade.

Figure 2
The CaMKIV Activity Cycle

PART I: STUDIES OF CASCADES INVOLVING CaMKKβ AND CaMKIV OR CaMKI

CaMK Cascade-Regulated Hippocampal Memory Formation

The first study I examined for “The Year in Calmodulin Kinase Cascades” has to do with hippocampal memory formation. It had previously been reported that CaMKIV played an important role in fear memory using CaMKIV knock-out mice (3). More recently, the group led by K. Peter Giese used mice null for CaMKKβ and found that it too played an important role in fear memory (4). In response to a foot shock, a type of contextural fear conditioning, activity is stimulated in hippocampal neurons, which, in turn, results in an increase in intracellular calcium. The calcium then binds calmodulin and the calcium-calmodulin complex activates CaMKKβ and CaMKIV. CaMKKβ phosphorylates and activates CaMKIV, which translocates into the nucleus. The primary substrate in this particular signaling complex is the cAMP response element-binding protein (CREB). When CREB is phosphorylated, it activates a number of genes, including two splicing factors called Srp 20 and Psf. Interestingly, the Srp 20 effect is gender specific, being only observed in male mice, whereas regulation of Psf occurs in mice of both sexes. Although not addressed in this paper, Srp 20 splices the microtubule-associated protein Tau, which enables Tau to alter the state of polymerization of microtubules, particularly in neuronal dendrites. Regardless, alternative splicing is an important regulatory mechanism for neuronal plasticity, and long-term memory formation is one outcome of such plasticity.

CaMK Cascade-Regulated Cell Survival

The next study, which came from a group in Italy, investigates a calcium-dependent pathway that is involved in regulation of cell survival (5). It involves much the same pathway as was described in the previous study but, in this case, lipopolysaccharide (LPS), the bacterial endotoxin, stimulates dendritic cells through toll-like receptor 4. Dendritic cells are antigen-presenting cells that mediate the primary adaptive immune response and are important to achieve tolerance toward self-antigens. LPS stimulation of dendritic cells causes an increase in intracellular calcium resulting in an increase in the calcium-calmodulin complex. As in the previous signaling complex, calcium-calmodulin activates CaMKKβ and CaMKIV, CaMKKβ phosphorylates CaMKIV, and CaMKIV phosphorylates CREB. Here, a primary target of CREB is the B-cell lymphoma protein 2 (BCL-2) gene, and BCL-2 is important in the regulation of cell survival. In mice null for CaMKIV (data not shown) or CaMKKβ, LPS fails to activate dendritic cells, and so the dendritic cells do not survive. Because the life span of dendritic cells is essential to control the number of these cells that display antigens in the T-cell zone, the authors suggest it to be likely that this CaMK cascade is important to regulate both quality and magnitude of the adaptive immune response.

CaMK Cascade-Regulated Neuronal Migration

This 2008 study, using mice null for either CaMKKβ or CaMKIV, shows the regulation of neuronal migration by a CaMK cascade. Immediately after birth, cerebellar granule cells are located in the external layer of the cerebellum where they proliferate during the first few days postpartum. Within the first 2 wk in mice, these cells cease proliferating, differentiate, and migrate into the internal granule layer of the cerebellum where they send out processes that connect with the Purkinje cells. The migration of these cells follows a gradient of neurotropins such as the brain-derived neurotropin growth factor (BDNF) that is, at least in part, produced from the cerebellar granule cells. The pathway that regulates this developmentally important process requires stimulation of the N-methyl-d-aspartic acid receptor, which, in turn, increases intracellular calcium. As in the other pathways discussed, calcium binds calmodulin, and the calcium-calmodulin complex activates the CaMKKβ-CaMKIV signaling complex, which results in the autonomously active form of CaMKIV entering the nucleus where it phosphorylates CREB. In this case activated CREB regulates the production of BDNF mRNA. This study used not only in vivo experiments but cerebellar microexplants and isolated cerebellar granule cell precursors as well. It demonstrates that all of the events described occur in all three types of systems and require both CaMKKβ and CaMKIV.

CaMK Cascade-Regulated Synaptogenesis

Processes regulated by CaMKI have not been studied nearly as much as those regulated by CaMKIV. The next study from Tom Soderling of the Vollum Institute is a good example of a CaMKI-dependent process. This paper shows that neuronal activity, again working through the N-methyl-d-aspartic acid receptor, but in hippocampal neurons rather than cerebellar granule neurons, causes the now-familiar increase in calcium, calmodulin, and CaMKKβ, but here the substrate of CaMKKβ is CaMKI (6). The study was conducted with isolated hippocampal slices, using shRNA to down-regulate CaMKI or CaMKKβ. The CaMKKβ-CaMKI complex recruits the G protein-coupled receptor kinase-interacting protein 1, which binds to the N-terminal region of CaMKKβ. G protein-coupled receptor kinase-interacting protein 1 functions as a scaffold for βPIX, which is a guanyl nucleotide exchange factor. The phosphorylation of βPIX by CaMKKβ triggers the recruitment of the small G-protein, Rac, and this, in turn, activates Rac by promoting the exchange of GDP by GTP. The GTP-bound form of Rac now stimulates the protein kinase PAK, which phosphorylates substrates (not evaluated here) that lead to changes in the actin/cytoskeleton to promote spine formation and synaptogenesis.

PART II: STUDIES OF CASCADES WITH CaMKKβ AND AMPK

AMPK Background

Both exercise and a lack of nutrients cause stress resulting in an increase in the AMP to ATP ratio. When that happens, an AMP-dependent kinase kinase (AMPKK) is activated to phosphorylate AMPK. AMPK is a heterotrimer with a catalytic α-subunit, a ß-subunit that serves as a scaffold, and a γ-subunit that is the AMP/ATP binding subunit. Stimulating the activity of AMPK in turn stimulates ß-oxidation, glycolysis, glucose transport, and food intake, while inhibiting protein synthesis, fatty-acid synthesis, and glucose-regulated gene transcription. Reactivating this pathway helps to replenish ATP in the cells. This phenomenon has been extensively studied in liver and skeletal muscle in response to exercise or high-fat diets (7).

The prototypic AMPKK is LKB1, the molecule that is mutated in the cancer susceptibility syndrome, Peutz-Jehgers. LKB1 phosphorylates Thr-172 in the activation loop of the catalytic subunit of heterotrimeric AMPK. It is the LKB1/AMPK pathway that is activated by an increase in the AMP:ATP ratio in liver and skeletal muscle. In 2005 it was shown that CaMKK can also serve as an AMPKK in cells, and it is likely that this function is unique to CaMKKβ (8). In this case, the process that leads to activation of AMPK is initiated by an increase in intracellular calcium and does not respond to changes in the AMP:ATP ratio. Contrariwise, the LKB1 complex is sensitive to AMP but not calcium. Thus, the CaMKK and LKB1 complexes with AMPK are distinct in that the CaMKKβ version of the complex lacks the AMPK γ-subunit so that calcium/calmodulin becomes the allosteric activator rather than AMP (9). What is interesting about the differences in these two complexes is that the CaMKKβ complex is particularly pervasive in brain and blood cells whereas the LKB1 complex is found in most peripheral organs involved in regulating energy balance such as liver and the striated muscles.

Interestingly, it has been reported recently that a 20-amino acid segment in the kinase domain of CaMKKβ called the “RP domain” is required for CaMKKβ binding to AMPK but not to its other substrates, CaMKI or CaMKIV (9). On the other hand, CaMKKα does not bind AMPK but does contain an RP domain that is important for its interaction with CaMKI and CaMKIV. These data reveal that a very small region of each CaMKK can differentially regulate substrate recognition and complex formation. The remaining papers I have chosen to discuss involve cellular processes affected by the CaMKKβ/AMPK cascade.

CaMK Cascade-Regulated Autophagy

The first study in this section on the CaMKKβ/AMPK cascade has particular relevance for endocrinology because its stimulus is vitamin D3, which is reported to regulate autophagy in the human breast cancer cell line, MCF-7 (10). Autophagy is an evolutionary conserved lysosomal pathway that functions in the turnover of long-lived macromolecules and organelles. This process is important for many cell functions such as nutrient delivery, remodeling, and differentiation as well as to remove damaged molecules or organelles. It was previously known that the yeast ortholog, Snf1, was a positive regulator of autophagy and, in mammalian cells AMPK negatively regulates the mammalian target of rapamycin (mTOR) pathway, and mTOR activation inhibits autophagy. The current study was prompted by the observations that vitamin D can induce autophagy and increase intracellular calcium coupled with the recent observations that increased calcium can activate AMPK via CaMKKβ. Indeed, vitamin D3 is shown to increase calcium when added to MCF-7 cells. The calcium leads to an increase in the calcium-calmodulin complex, which activates CaMKKβ, and CaMKKβ phosphorylates and activates AMPK. This cytoplasmic signaling complex phosphorylates tuberous sclerosis protein 2, which consequently interacts with Ras homolog enriched in brain protein (Rheb) leading to the activation of mTOR, which triggers autophagy. In the absence of CaMKKβ, in this case done by shRNAs, there is a marked suppression of autophagy. However, it remains to be determined whether the CaMKKβ/AMPK effect on mTOR is sufficient to increase autophagy or whether additional calcium-dependent pathways act in parallel.

CaMK Cascade-Mediated, CO2-Induced Alveolar Epithelial Dysfunction

The next study explores hypercapnia, specifically, how carbon dioxide (CO2) results in alveolar epithelial dysfunction (11). The study shows that this process also involves a calmodulin cascade. Hypercapnia (excess CO2 in the blood) increases calcium in alveolar epithelial cells. The calcium then binds calmodulin to initiate the signaling cascade that leads to impaired alveolar fluid reabsorption. The calcium-calmodulin complex activates CaMKKβ, which promotes its association with AMPK in the cytoplasm. The CaMKKβ-AMPK complex associates with and phosphorylates protein kinase C-ζ. Protein kinase C-ζ phosphorylates the plasma membrane-associated sodium potassium adenosine triphosphatase, triggering its endocytosis, which blocks both sodium transport and alveolar fluid clearance. This study of human cells (rather than mouse cells), used small interfering RNA to down-regulate or STO-609 to inhibit CaMKKβ as well as compound C or a dominant-negative form of the AMPK catalytic subunit to inhibit AMPK. This is an interesting advance in the concept of CO2 sensing that links it to rapid changes in calcium leading to CaMKKβ-dependent activation of AMPK. The elucidation of this signaling pathway is important because the mammalian alveolar epithelium is the site of CO2 elimination, and any inhibition of this process is very likely to have pathophysiological consequences.

CaMK Cascade-Regulated Fatty Acid Oxidation

Also investigating a steroid hormone (T3), the next study uses four cell types (C2C12, FRTC-2, 3T3-L1, and HeLa) rather than just one and derives the same findings in all four (12). T3 stimulates phospholipase C, resulting in increased inositol triphosphate, which releases calcium from the endoplasmic reticulum to bind calmodulin. Again, it’s a cytoplasmic signaling complex, in which CaMKKβ phosphorylates AMPK, which phosphorylates acetyl-coenzyme A (CoA) carboxylase (ACC), which is its primary substrate in the pathway that leads to fatty acid oxidation. ACC functions to regulate the accumulation of malonyl-CoA, which leads to increased mitochondrial fatty acid oxidation. The search for exactly how T3 signals through its receptor to promote nongenomic actions influencing mitochondrial function has been going on for many years. The results of this study, however, are convincing and suggest that fatty acid oxidation may be one answer to this intriguing question.

CaMK Cascade-Regulated Energy Balance

This last study from my own laboratory demonstrates the regulation of energy balance by a CaMK cascade in hypothalamic neurons present in the arcuate nucleus (9). Previous studies of this pathway had shown that ghrelin interacts with the ghrelin receptor present on these neuropeptide Y (NPY) neurons, which activates phospholipase C to increase inositol triphosphate to, in turn, increase intracellular calcium. This leads to an activation of AMPK, although the steps between increased calcium and AMPK had not been investigated. The increased AMPK activity is important to trigger, by an unknown mechanism, transcription of the genes encoding NPY and Agouti-related peptide (AgRP), which are two orexigenic peptides that affect energy balance (7).

What this new study reveals is that in hypothalamic NPY neurons, CaMKKβ is the calcium-dependent enzyme that links the ghrelin-induced increase in intracellular calcium to the activation of AMPK to the production of NPY/AgRP (9). In addition, the CaMKKβ/AMPK signaling complex phosphorylates ACC, which stimulates long-chain CoA fatty acid oxidation (as seen in the last study), which has been reported to result in the closure of ATP-dependent potassium channels and depolarization of the plasma membrane of NPY neurons. Incidentally, these are exactly the same ATP-dependent potassium channels that are regulated by glucose metabolism in pancreatic β-cells and are the targets of the sulfonylureas used to treat type 2 diabetes. At any rate, the concerted actions of ghrelin on NPY neurons conspire to increase food intake, and CaMKKβ is important to this process.

Whereas the ghrelin pathway in NPY neurons leading to increased food intake involves CaMKKβ and increased activity of AMPK, this pathway is opposed by the action of leptin acting on the same neurons. Leptin, working through the leptin receptor OBRb, stimulates a signaling pathway that results in decreased AMPK phosphorylation and activity, presumably via stimulation of an AMPK phosphatase (7). This, in turn, results in decreased production of NPY/AgRP and a resulting suppression of food intake. What happens in mice null for CaMKKβ is that the ghrelin pathway is suppressed while they remain leptin sensitive. CaMKKβ null and wild-type (WT) mice were placed on high-fat or control low-fat diets at weaning and fed these diets for 9 months. Whereas even on the low-fat diet the CaMKKβ mice ate and weighed less that did WT mice, when fed the high-fat diet, the CaMKKβ are less than half the size of the WT mice fed the same chow. Even more remarkable is that the CaMKKβ null mice remain insulin sensitive and glucose tolerant whereas the WT mice, predictably, develop the insulin resistance and hyperglycemia typical of type 2 diabetes. Thus, the deletion of the CaMKKβ gene results in resistance to high-fat diet-induced obesity and diabetes. Because CaMKKβ is not normally expressed in liver, heart, or skeletal muscle, these results suggest that inhibition of CaMKKβ in the brain might be an attractive avenue to explore therapeutically.

Figure 33 presents a diagram that suggests two different pathways involving AMPK may be important in the regulation of energy balance (8). The right side depicts cell activation, for example, exercise in muscle, which produces metabolic stress, resulting in a decrease in the concentration of ATP and a corresponding increase of AMP. In this case LKB1 serves as the AMPKK, and the results of this pathway are beneficial effects on body composition. On the other hand, the left side shows a second type of activation that is systemic, in which ghrelin, acting in the hypothalamus, stimulates a Gq-coupled receptor to increase intracellular calcium in NPY neurons. This activates CaMKKβ to phosphorylate AMPK, thereby increasing food intake resulting in a negative effect on body composition.

Figure 3
Metabolic Economy and AMPK Activation

CONCLUDING REMARKS

In the world of CaMK cascades, the discovery of AMPK as a substrate for CaMKKβ has led to exciting insight into how a variety of cellular functions are regulated. The pharmacological industry has been searching for small molecules activators of AMPK for some time. One reason for this effort is that problems in liver or in skeletal muscle that result in decreased ATP can be ameliorated by AMPK activation as the pathway resulting in fatty acid oxidation works to replenish ATP. On the other hand, depleting the brain of ATP would have devastating consequences. Consider that the most pervasive messenger in the brain is calcium, however, and the brain has evolved to use calcium in the pathway that regulates AMPK. In this case, increased hypothalamic AMPK increases food intake. Rather than inhibiting AMPK, which would not be indicated systemically due to its negative effects on body composition, inhibition of CaMKKβ would act centrally to inhibit AMPK, which, in turn, decreases food intake. Indeed, treating mice with the one CaMKKβ inhibitor that is currently available, STO-609, also leads to reduced food intake and decreased body weight (9). It remains for researchers to turn their attention to discover novel agents that specifically inhibit CaMKKβ as a potential way to combat both obesity and type 2 diabetes. The next year in CaMK cascades should be very exciting.

Supplementary Material

[Supplemental Audio File]

Acknowledgments

I thank the members of my laboratory whose research efforts are exemplary.

Footnotes

This work was supported, in part, by National Institutes of Health Grants GM-33976 and DK-074701.

This commentary is based on a talk presented at ENDO 2008, San Francisco, CA, on Monday, June 16, 2008. Draft prepared by Kelly Horvath.

Disclosure Statement: A.R.M. has received lecture fees and has a patent pending.

First Published Online October 9, 2008

Abbreviations: ACC, Acetyl-CoA carboxylase; AgRP, Agouti-related peptide; AMPK, AMP-dependent kinase; AMPKK, AMPK kinase; BDNF, brain-derived neurotropin growth factor; CaMK, calmodulin kinase; CaMKK, CaMK kinase; CoA, coenzyme A; CREB, cAMP response element-binding protein; LPS, lipopolysaccharide; NPY, neuropeptide Y; mTOR, mammalian target of rapamycin; PP2A, protein phosphatase 2A; WT, wild type.

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