Lobe specific Ca2+-calmodulin nano-domain in neuronal spines: a single molecule level analysis
| Autor: | Yoshihisa Kubota, M. Neal Waxham |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Biophysics/Theory and Simulation
Models Molecular Dendritic spine Calmodulin Dendritic Spines Computational Biology/Computational Neuroscience Hippocampal formation Models Biological Cell Biology/Cell Signaling 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Ca2+/calmodulin-dependent protein kinase Biochemistry/Cell Signaling and Trafficking Structures Neuroscience/Neuronal Signaling Mechanisms Genetics Animals Neuroscience/Theoretical Neuroscience CA1 Region Hippocampal Molecular Biology lcsh:QH301-705.5 Ecology Evolution Behavior and Systematics 030304 developmental biology 0303 health sciences Computational Biology/Systems Biology Biochemistry/Theory and Simulation Ecology biology Pyramidal Cells Long-term potentiation Anatomy Chemical Biology/Chemical Biology of the Cell Receptor–ligand kinetics Rats Computational Theory and Mathematics lcsh:Biology (General) Modeling and Simulation Second messenger system Synaptic plasticity Biophysics biology.protein Calcium Monte Carlo Method Algorithms 030217 neurology & neurosurgery Research Article |
| Zdroj: | PLoS Computational Biology, Vol 6, Iss 11, p e1000987 (2010) PLoS Computational Biology |
| ISSN: | 1553-7358 |
| Popis: | Calmodulin (CaM) is a ubiquitous Ca2+ buffer and second messenger that affects cellular function as diverse as cardiac excitability, synaptic plasticity, and gene transcription. In CA1 pyramidal neurons, CaM regulates two opposing Ca2+-dependent processes that underlie memory formation: long-term potentiation (LTP) and long-term depression (LTD). Induction of LTP and LTD require activation of Ca2+-CaM-dependent enzymes: Ca2+/CaM-dependent kinase II (CaMKII) and calcineurin, respectively. Yet, it remains unclear as to how Ca2+ and CaM produce these two opposing effects, LTP and LTD. CaM binds 4 Ca2+ ions: two in its N-terminal lobe and two in its C-terminal lobe. Experimental studies have shown that the N- and C-terminal lobes of CaM have different binding kinetics toward Ca2+ and its downstream targets. This may suggest that each lobe of CaM differentially responds to Ca2+ signal patterns. Here, we use a novel event-driven particle-based Monte Carlo simulation and statistical point pattern analysis to explore the spatial and temporal dynamics of lobe-specific Ca2+-CaM interaction at the single molecule level. We show that the N-lobe of CaM, but not the C-lobe, exhibits a nano-scale domain of activation that is highly sensitive to the location of Ca2+ channels, and to the microscopic injection rate of Ca2+ ions. We also demonstrate that Ca2+ saturation takes place via two different pathways depending on the Ca2+ injection rate, one dominated by the N-terminal lobe, and the other one by the C-terminal lobe. Taken together, these results suggest that the two lobes of CaM function as distinct Ca2+ sensors that can differentially transduce Ca2+ influx to downstream targets. We discuss a possible role of the N-terminal lobe-specific Ca2+-CaM nano-domain in CaMKII activation required for the induction of synaptic plasticity. Author Summary Calmodulin is a versatile Ca2+ signal mediator and a buffer in a wide variety of body organs including the heart and brain. In the brain, calmodulin regulates intracellular molecular processes that change the strength of connectivity between neurons, thus contributing to various brain functions including memory formation. The exact molecular mechanism as to how calmodulin regulates these processes is not yet known. Interestingly, in other excitable tissues, including the heart, each of two lobes of calmodulin responds differentially toward Ca2+ influx and toward its target molecules (e.g., ion channels). This way, calmodulin precisely controls the Ca2+ dynamics of the cell. We wish to test if a similar mechanism may be operational in neurons so that two lobes of calmodulin interact differentially with Ca2+ ions to activate different downstream molecules that control the strength of connections between neurons. We constructed a detailed simulation of calmodulin that allows us to keep track of its interactions with Ca2+ ions and target proteins at the single molecule level. The simulation predicts that two lobes of calmodulin respond differentially to Ca2+ influx both in space and in time. This work opens a door to future experimental testing of the lobe-specific control of neural function by calmodulin. |
| Databáze: | OpenAIRE |
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