DBP2: Regulation and binding to PSD-95 and its relation to AMPA receptor trafficking
PI:Mary Kennedy, PhD, the Allen and Lenabelle Davis Professor of Biology, California Institute of Technology
Funding Source(s): 5R01MH095095-04, Time resolved assay of synaptic enzyme activity by mass spectrometry; 7/1/11-4/30/16 (Kennedy); Caltech Institutional Funds (Kennedy)
How the DBP acts as a driver of test bed:
This project will drive development of the spatial extensions to BioNetGen Language (BNGL) for MCell in two ways, by enabling MCell to deal with combinatorial complexity of the multiple interactions of PDZ domain, and by allowing to including trans-synaptic interactions
Our goal is to collect and integrate anatomical, biochemical and physiological data to permit construction and testing of spatially accurate models of signal transduction pathways in the postsynaptic dendritic spine, and to identify and simulate critical dynamic interactions following the influx of Ca2+ into the spine. Our initial focus is on activation and (auto)regulation of the key enzyme calcium/calmodulin-dependent protein kinase II (CaMKII)
We have two specific aims:
Construct realistic computational models of activation of CaMKII and phosphorylation of its substrates in the spine under a wide variety of conditions.
The models will be constrained by measurements of kinetic parameters in our lab, supported by a grant from NIDA, and by measurements of the dynamics of phosphorylation in brain slices (Aim 2) using new experimental tools that we are developing, supported by a grant from NIMH.
Design and carry out experiments to measure the flow of information through calcium-triggered biochemical regulatory pathways in the spine that are involved in induction of long-term potentiation and depression, focusing initially on CaMKII and its substrates.
Compare experimental results to models created in MCell to identify gaps in our understanding and to enable creation of successively more accurate models.
Publications resulting from this work
- Bartol TM, Keller DX, Kinney JP, Bajaj CL, Harris KM, Sejnowski TJ, Kennedy MB (2015) Computational reconstitution of spine calcium transients from individual proteins Front Synaptic Neurosci. 7:17 PMID: 26500546, PMC4595661
- Bartol TM, Keller DX, Kinney JP, Bajaj CL, Harris KM, Sejnowski TJ, Kennedy MB (2015) Nanoconnectomic upper bound in the variability of synaptic plasticity Elife 4.pii: e10778 PMID: 26618907, PMC4737657
- Stefan MI, Bartol TM, Sejnowski TJ, Kennedy MB (2014) Multi-state modeling of biomolecules PLoS Comp Biol. 10(9):e1003844. PMID: 25254957, PMC4201162