CaM Kinase: A Model for its Activation and Dynamics

Multifunctional calmodulin kinase (CaM kinase) is an enzyme which transduces fluctuations of intracellular calcium ion concentrations into kinase activity. The enzyme phosphorylates a variety of target proteins. Activation of CaM kinase requires the formation of a calcium—calmodulin complex and binding by the complex to one of ten identical subunits of the holoenzyme. The CaM kinase enzyme is a ring. Each subunit in the ring traverses a path between five distinct activation states. Transitions between activation states depend upon the dynamic calcium—calmodulin complex levels, binding and release of the complex to the subunitsʹ activation sites, and the activation status of the right-hand neighboring subunit in the ring. The dynamic distribution of a given subunitʹs state is modeled using a conditional (conditioned upon the neighborʹs status), finite state, non-homogeneous Markov process. A simulation package for enzyme activation has been developed, and initial studies with one calcium spike, low-frequency—low-amplitude sinusoids, and spike trains are presented. The capability of the CaM kinase molecule to act as an information processor, translating short-term calcium fluctuations into long-term activation (i.e. "memory") is discussed.