Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca²⁺-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.

The Ca²⁺-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes, and activates them. For example, the Ca²⁺-CaM complex activates a family of protein kinases called Ca²⁺ calmodulin-dependent kinases (CaM kinases). CaM kinases phosphorylate target proteins such as transcription factors and alter their gene expression.

One such CaM kinases are CaM kinase II which is abundantly present in the nervous system. They consist of a stack of two giant rings, where each ring contains six copies of the enzyme. The enzyme has two domains, the kinase domain and the hub domain. A regulatory segment inhibits the kinase activity of the enzyme, keeping it in an inactive state.

The binding of the Ca²⁺-CaM complex to the regulatory segment unlocks the enzyme from an inactive to an active state. The Ca²⁺-CaM complex also activates nearby kinase domains that have popped out from its hub domain. The activated kinase domains of adjacent enzymes phosphorylate each other’s regulatory segments by autophosphorylation. Autophosphorylated CaM kinase II stays active even after the decay of the calcium signal. This allows the activated kinase to be a memory trace of a previous calcium spike and function as a memory device of the nervous system. Once protein phosphatase removes phosphates from the regulatory segment, CaM kinase II is switched off.

CaM kinase II can also decipher frequency changes in the calcium oscillations. At a low frequency of Ca²⁺ spikes, kinase becomes inactive as autophosphorylation cannot keep the enzyme active until the subsequent Ca²⁺ spikes. At a high frequency of Ca²⁺ spikes, the enzyme becomes only partially inactive between each Ca²⁺ spike. This leads to a progressive increase in the enzyme’s catalytic activity until it becomes maximally active when all of its domains are autophosphorylated.