title: Lobe specific Ca2+-calmodulin nano-domain in neuronal spines: a single molecule level analysis.
abstract: 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.
authors.affiliation: Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas, USA. Yoshihisa.Kubota@uth.tmc.edu
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kubota
authors.forename: M Neal
authors.initials: MN
authors.lastname: Waxham
mesh_terms: D000465:Algorithms; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D009010:Monte Carlo Method; D017966:Pyramidal Cells / Q000502:physiology; D051381:Rats
chemical_list: D002147:Calmodulin; D002118:Calcium