A recent review published within 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 goal. By targeting this protein-coding enzyme, CaMKK2, which is related to many neuronal and metabolic processes, scientists may have the opportunity to develop recent treatment strategies for bipolar disorder.

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

Current approaches to treat bipolar disorder

At the very least one in every 100 people is affected by bipolar disorder, which may result in severe episodes of mania, depression, or each. Bipolar disorder is related to cognitive and functional disabilities, the next risk of metabolic and cardiovascular diseases, and lower life expectancies; nonetheless, treatment options remain inadequate. Lithium and valproate are common drugs used to treat bipolar disorder; nonetheless, the pathways through which these compounds function aren’t well understood.

To treat bipolar disorder, doctors depend on a cocktail of medicines which might be expensive, can have harmful interactions with one another, and cause negative negative effects, including frequent mood swings. Because of this, many patients change medications or may even discontinue taking them.

While there may be a transparent need for simpler treatments for bipolar disorder, developing higher therapies requires scientists to raised 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, because it has vital functions in neurotransmitter release and gene expression. Since these functions help us learn and control our mood, behavior, and memory, defective calcium signaling may 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 make use of calcium channel blockers to treat the condition with little success. Recent studies on mice have reported an alternate view that led scientists to imagine that bipolar disorder could also be related to lower calcium activity within 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 on this condition remain unclear.

CaMKK2 and brain functioning

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

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

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

CaMKK2 and mood stabilizers

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

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

CaMKK2 and metabolic dysfunction

Bipolar disorder is related to a greater incidence of type 2 diabetes and metabolic syndrome, which reflects a link between bipolar disorder and metabolic dysfunction. Some metabolic aberrations on 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 an unlimited amount of existing literature, the authors propose the CaMKK2 signaling pathway as a promising goal for bipolar disorder treatment. The involvement of the CaMKK2 pathway in critical points of bipolar disorder, comparable to signal transduction defects, genetic aspects, metabolic dysfunction, and the motion 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 assist develop small-molecule drugs that activate neuronal CaMKK2, which may lead to the event of higher treatment approaches for bipolar disorder.

Just like the revolution in psychiatry sparked by the invention of the effectiveness of lithium, the event of recent mechanism-based therapies with superior efficacy and tolerability hold great promise to similarly transform the treatment of bipolar disorder.”

Journal reference:

• Kaiser, J., Nay, K., Horne, C.R., et al. (2023). CaMKK2 as an emerging treatment goal for bipolar disorder. Molecular Psychiatry. doi:10.1038/s41380-023-02260-3,