CaMKK2 as an emerging treatment target for bipolar disorder

Abstract

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca²⁺-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder.

Fig. 1. The CaMKK2 signalling pathway in the brain.

CaMKK2 is activated endogenously by voltage-gated Ca²⁺-channels (Ca_v1.2), in addition to neurotransmitter and hormone receptors that increase intracellular Ca²⁺ and cause accumulation of the Ca²⁺-calmodulin (Ca²⁺-CaM) complex. It can also be activated exogenously by the mood-stabiliser drug, lithium (Li⁺). Conversely, CaMKK2 is inhibited by CDK5 and GSK3, as well as by hormones that stimulate PKA signalling such as glucagon-like peptide-1 (GLP-1). Activated CaMKK2 directly phosphorylates three known downstream effectors (CaMK1, CaMK4 and AMPK) through which it regulates a range of neuronal and metabolic processes that support brain function.

Fig. 2. Domain structure and upstream mechanisms that regulate CaMKK2 activity.

Linear schematic of the domain structure of human CaMKK2 illustrating the position of the catalytic kinase domain, the autoinhibitory (AIS) and calmodulin-binding sequences (CaMBS), and regulatory phosphorylation sites, as well as the bipolar disorder-linked T85S polymorphism and rare R311C mutation (green). Autophosphorylation of Thr85 and Thr482 (yellow) increase CaMKK2 activity. In the S3 node, phosphorylation of Ser137 (red) by CDK5 primes CaMKK2 for sequential phosphorylation on Ser133 and Ser129 (blue) by GSK3, which results in CaMKK2 inhibition. Phosphorylation of Ser100, Ser495 and Ser511 (magenta) by PKA prevents CaMKK2 activation by Ca²⁺-calmodulin, and causes binding of 14-3-3 adaptor proteins that keep CaMKK2 in an inactivated state.