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Calmodulin (CaM) is a ubiquitous Ca 2+  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 Ca 2+ -dependent processes that underlie memory formation: long-term potentiation (LTP) and long-term depression (LTD). Induction of LTP and LTD require activation of Ca 2+ -CaM-dependent enzymes: Ca 2+ /CaM-dependent kinase II (CaMKII) and calcineurin, respectively. Yet, it remains unclear as to how Ca 2+  and CaM produce these two opposing effects, LTP and LTD. CaM binds 4 Ca 2+  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 Ca 2+  and its downstream targets. This may suggest that each lobe of CaM differentially responds to Ca 2+  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 Ca 2+ -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 Ca 2+  channels, and to the microscopic injection rate of Ca 2+  ions. We also demonstrate that Ca 2+  saturation takes place via two different pathways depending on the Ca 2+  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 Ca 2+  sensors that can differentially transduce Ca 2+  influx to downstream targets. We discuss a possible role of the N-terminal lobe-specific Ca 2+ -CaM nano-domain in CaMKII activation required for the induction of synaptic plasticity.

Lobe Specific Ca2+-Calmodulin Nano-Domain in Neuronal Spines: A Single Molecule Level Analysis