Paper Info
Title
Lobe specific Ca2+-calmodulin nano-domain in neuronal spines: a single molecule level analysis.
Abstract
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.
Year
DOI
Venue
2010
10.1371/journal.pcbi.1000987
PLOS COMPUTATIONAL BIOLOGY
Keywords
Field
DocType
gene transcription,biological,dendritic spine,monte carlo method,monte carlo simulation,second messengers,calcium,kinetics,synaptic plasticity,long term depression,molecular,dendritic spines,enzyme,point pattern analysis,hippocampal,long term potentiation,calmodulin,n terminal,algorithms
Long-term potentiation,Anatomy,Dendritic spine,Biology,Biophysics,Calmodulin,Receptor–ligand kinetics,Ca2+/calmodulin-dependent protein kinase,Synaptic plasticity,Genetics,Hippocampal formation,Second messenger system
Journal
Volume
Issue
ISSN
6
11
1553-7358
Citations 
PageRank 
References 
1
0.48
4
Authors
2
Name
Order
Citations
PageRank
Y Kubota1368.75
M Neal Waxham2233.83