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.
Highlights
Calmodulin (CaM) is a ubiquitous Ca2+ buffer and signaling molecule in cells
The simplest correlative explanation for these results is that long-term depression (LTD) is induced by intermediate levels of Ca2+ that activate CaM and subsequently calcineurin but not CaM-dependent protein kinase II (CaMKII)
A single stochastic Ca2+ channel was placed on the top of the head of a standard spine. This channel injects Ca2+ at a given rate and we examine the relation between the Ca2+ injection rate and the spatio-temporal profile of Ca2+ transients in the spine
Summary
Calmodulin (CaM) is a ubiquitous Ca2+ buffer and signaling molecule in cells. In the excitatory synapse of hippocampal CA1 pyramidal neurons, the activation of CaM dependent enzymes results in the induction of synaptic plasticity (e.g., long-term potentiation (LTP) and long-term depression (LTD)) [1]. The induction of NMDA receptor dependent LTP and LTD require increased Ca2+ and subsequent activation of CaM-dependent downstream enzymes: CaM-dependent protein kinase II (CaMKII) and calcineurin. Injection of CA1 pyramidal cells with peptides that block CaMKII activity inhibited the induction [2,3], but not maintenance [4] of LTP, while injection of the activated form of the enzyme produced LTP-like plasticity [5,6]. Higher levels of Ca2+ initiate CaM-dependent CaMKII activation and autophosphorylation, leading to LTP induction. It is still unknown how Ca2+ and CaM regulate two opposing processes as distinct as LTP or LTD in such a precise and controlled manner
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