CACR Seminar “Models of interactions of Ca(2+), CaM, and monomeric catalytic subunits of CaMKII: a piece of the post-synaptic signaling network puzzle”

Monday, Oct. 27, 11:00AM
Moore 080

“Models of interactions of Ca(2+), CaM, and monomeric catalytic subunits of CaMKII: a piece of the post-synaptic signaling network puzzle”
Dr. Shirley Pepke, Caltech Center for Advanced Computing Research

Calcium (Ca) signal transduction is a fundamental driver of synaptic plasticity in neurons. The molecule Calmodulin (CaM) is an important second messenger in Ca signaling in the post-synaptic density, integrating Ca levels via four binding sites. CaM transmits Ca signal information downstream through selective binding to target enzymes such as calmodulin-activated kinase II (CaMKII). Prior models of Ca/CaM/CaMKII have focused on the role of the unique holoenzyme structure of CaMKII in generating sensitivity and selectivity in response to dynamic Ca input. I will present models of Ca/CaM/CaMKII binding and phosphorylation reactions (developed within the Kennedy lab) that incorporate detailed representations of Ca/CaM and Ca/CaM/CaMKII binding states and explore the resulting impact on phosphorylation rates of monomeric catalytic subunits of CaMKII. Ca/CaM state models are seen to be necessary to accurately predict CaMKII phosphorylation levels under the low Ca conditions that are typical in neurons. Additionally, specific kinetic rate ranges in the models are shown to confer frequency sensitivity independent of a CaMKII holoenzyme structure. Sensitivity analysis on the estimated model parameters confirm these findings across sampled ranges of all parameters and point to areas where further experiments are necessary to establish quantitative values. While the results presented will be for numerical integration of an ODE representation of the reaction network, the models are easily implemented within a stochastic simulation framework that allows analysis of the response to Ca inputs with low molecule numbers as well as gradients in both time and space. The models promise new insight into the relative roles of thermodynamics, kinetics, molecular structure, and spatial distributions of signaling proteins in determining the synaptic response to Ca influxes.