Could CaMKK2 enzyme be the key to treating bipolar disorder?

By Priyanjana Pramanik, MSc.Reviewed by Benedette Cuffari, M.Sc.Sep 24 2023

A recent review published in the journal Molecular Psychiatry explores the calcium-calmodulin-dependent protein kinase kinase-2 (CaMKK2) signaling pathway as a contributor to bipolar disorder pathogenesis and key treatment target. By targeting this protein-coding enzyme, CaMKK2, which is associated with many neuronal and metabolic processes, scientists may be able to develop new treatment strategies for bipolar disorder.

Study: CaMKK2 as an emerging treatment target for bipolar disorder. Image Credit: Tunatura / Shutterstock.com

Current approaches to treat bipolar disorder

At least one in every 100 people is affected by bipolar disorder, which can lead to severe episodes of mania, depression, or both. Bipolar disorder is associated with cognitive and functional disabilities, a higher risk of metabolic and cardiovascular diseases, and lower life expectancies; however, treatment options remain inadequate. Lithium and valproate are common drugs used to treat bipolar disorder; however, the pathways through which these compounds function are not well understood.

To treat bipolar disorder, doctors rely on a cocktail of medications that are expensive, may have harmful interactions with each other, and cause negative side effects, including frequent mood swings. As a result, many patients change medications or may even discontinue taking them.

While there is a clear need for more effective treatments for bipolar disorder, developing better therapies requires scientists to better understand its causes at a cellular and molecular level.

The role of calcium ions

The signaling of calcium ions is critical for the functioning of the brain, as it has important functions in neurotransmitter release and gene expression. Since these functions help us learn and control our mood, behavior, and memory, defective calcium signaling could lead to certain neurological conditions like bipolar disorder.

Previous studies have shown that patients with bipolar disorder have higher levels of free intracellular calcium, which led scientists to use calcium channel blockers to treat the condition with little success. Recent studies on mice have reported an alternative view that led scientists to believe that bipolar disorder may be associated with lower calcium activity in the brain.

Despite considerable evidence demonstrating intracellular calcium abnormalities in bipolar disorder pathophysiology, the specifics of brain calcium signaling that causes the characteristic manic­-­­depressive behaviors in this condition remain unclear.

CaMKK2 and brain functioning

CaMKK2 is critical for a signaling pathway that regulates calcium and, as a result, essential brain functions like the formation of long-term memories, metabolic activities, behavior, and mood.

CAMKK2 messenger ribonucleic acid (mRNA) is highly expressed in many parts of the adult brain, including the basal ganglia, amygdala, cerebral cortex, cerebellum, hypothalamus, and hippocampus. The expression of the CAMKK2 gene is relatively low during early development but significantly increases during late childhood or early adulthood, which coincides with the age of bipolar disorder onset when many people begin to show symptoms.

CaMKK2 activation in mice increases the expression of a critical neuronal function regulator known as the brain-derived neurotrophic factor (BDNF). Humans with bipolar disorder exhibit lower BDNF levels during both manic and depressive phases, thus suggesting a lack of CaMKK2 activation. Several studies have reported that certain rare mutations and polymorphisms may reduce the functioning of CaMKK2 and trigger the development of bipolar disorder.

CaMKK2 and mood stabilizers

Mood stabilizers like lithium and valproate have been used to treat bipolar disorder; however, the underlying mechanisms of their action remain unclear. Studies have shown that lithium blocks glycogen synthase kinase-3 (GSK3)-phosphorylation of the S3-node and increases CaMKK2 activity leading to mood stabilization.

Studies on valproate have reported that this drug has multiple targets, including CaMKK2, which contributes to its mood-stabilizing properties. Thus, both lithium and valproate affect CaMKK2 at different levels, which indicates its role in their mechanisms of action in the treatment of bipolar disorder.

CaMKK2 and metabolic dysfunction

Bipolar disorder is associated with a greater incidence of type 2 diabetes and metabolic syndrome, which reflects a link between bipolar disorder and metabolic dysfunction. Some metabolic aberrations in this disorder resemble those observed in cells with low CaMKK2, including increased levels of brain lactate and elevated oxidative stress.

Conclusions

Based on evidence from a vast amount of existing literature, the authors propose the CaMKK2 signaling pathway as a promising target for bipolar disorder treatment. The involvement of the CaMKK2 pathway in critical aspects of bipolar disorder, such as signal transduction defects, genetic factors, metabolic dysfunction, and the action of mood stabilizers, justifies this hypothesis.

Several drugs targeting protein kinases like CaMKK2 are currently approved for clinical use. Structural studies and high-throughput screening can help develop small-molecule drugs that activate neuronal CaMKK2, which could lead to the development of better treatment approaches for bipolar disorder.

Like the revolution in psychiatry sparked by the discovery of the effectiveness of lithium, the development of new mechanism-based therapies with superior efficacy and tolerability hold great promise to similarly transform the treatment of bipolar disorder.”