Trinuclear Calcium Site in the C2 Domain of PKCα/γ Is Prone to Lithium Attack

Lithium (Li⁺) is the first-line therapy for bipolar disorder and a candidate drug for various diseases such as amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Despite being the captivating subject of many studies, the mechanism of lithium's therapeutic action remains unclear. To date, it has been shown that Li⁺ competes with Mg²⁺ and Na⁺ to normalize the activity of inositol and neurotransmitter-related signaling proteins, respectively. Furthermore, Li⁺ may co-bind with Mg²⁺-loaded adenosine or guanosine triphosphate to alter the complex's susceptibility to hydrolysis and mediate cellular signaling. Bipolar disorder patients exhibit abnormally high cytosolic Ca²⁺ levels and protein kinase C (PKC) hyperactivity that can be downregulated by long-term Li⁺ treatment. However, the possibility that monovalent Li⁺ could displace the bulkier divalent Ca²⁺ and inhibit PKC activity has not been considered. Here, using density functional theory calculations combined with continuum dielectric methods, we show that Li⁺ may displace the native dication from the positively charged trinuclear site in the C2 domain of cytosolic PKCα/γ. This would affect the membrane-docking ability of cytosolic PKCα/γ and reduce the abnormally high membrane-associated active PKCα/γ levels, thus downregulating the PKC hyperactivity found in bipolar patients.