Computational reconstitution of spine calcium transients from individual proteins

Abstract

We have built a stochastic model in the program MCell that simulates Ca2+ transients in spines from the principal molecular components believed to control Ca2+ entry and exit. Proteins, with their kinetic models, are located within two segments of dendrites containing 88 intact spines, centered in a fully reconstructed 6 × 6 × 5 μm3 cube of hippocampal neuropil. Protein components include AMPA- and NMDA-type glutamate receptors, L- and R-type voltage-dependent Ca2+ channels, Na+/Ca2+ exchangers, plasma membrane Ca2+ ATPases, smooth endoplasmic reticulum Ca2+ ATPases, immobile Ca2+ buffers, and calbindin. Kinetic models for each protein were taken from published studies of the isolated proteins in vitro. For simulation of electrical stimuli, the time course of voltage changes in the dendritic spine was generated with the desired stimulus in the program NEURON. Voltage-dependent parameters were then continuously re-adjusted during simulations in MCell to reproduce the effects of the stimulus. Nine parameters of the model were optimized within realistic experimental limits by a process that compared results of simulations to published data. We find that simulations in the optimized model reproduce the timing and amplitude of Ca2+ transients measured experimentally in intact neurons. Thus, we demonstrate that the characteristics of individual isolated proteins determined in vitro can accurately reproduce the dynamics of experimentally measured Ca2+ transients in spines. The model will provide a test bed for exploring the roles of additional proteins that regulate Ca2+ influx into spines and for studying the behavior of protein targets in the spine that are regulated by Ca2+ influx.

Interactions between calmodulin and neurogranin govern the dynamics of CaMKII as a leaky integrator

“…Ng has very different effects on these different species (Figure 3 binding proteins [46,3]. For this purpose we found, through trial and error, the concentration of Ca 2+ influx at the peak, in the absence of any Ca 2+ -binding molecules should reach ∼ 25−145 µM, depending on the presence of Ng and [CaM ], so that in our simulated conditions [Ca 2+ ] f ree = 10 µM at the peak.…”

“…transients in this spines become more dilute in response to back-propagating action potentials [3]. Thus we can say that integration of Ca 2+ signals is an in-built mechanism in the dendritic spine to down-regulate its sensitivity to these signals as the corresponding synapse grows larger.…”

Amyloid pathology disrupts gliotransmitter release in astrocytes

“…PMCA 68 k f1 = 15 µM -1 s -1 , k b1 = 20 s -1 , k f2 = 20 s -1 , k f3 = 100 s -1 , k l = 0.6 s -1 , PMCA density = 400 µm -2 Cytosol Ca 2+ buffer 100 k f = 60 µM -1 s -1 , k b = 1200 s -1 , buffer concentration = 50 µM SERCA 101 V max = 250 µMs -1 , k a = 100 nM, n = 2 ER-leak k l = 0.2 s -1 IP 3 receptor 51 a 1 = 400 µMs -1 , a 2 = 0.2 µM -1 s -1 , a 3 = 400 µM -1 s -1 , a 4 = 0.2 µM -1 s -1 , a 5 = 20 µM -1 s -1 , b 1 = 52 s -1 , b 2 = 0.2 s -1 , b 3 = 377.36 s -1 , b 4 = 0.02 s -1 , b 5 = 1.64 s -1 , ν max = 6.0 s -1 , n = 5 ER Ca 2+ buffer 102 kf1 = 1 µM -1 s -1 , kb1 = 80 s -1 , buffer concentration = 10 µM mGluR 103 V max = 0.65 µMs -1 , k a = 6 µM, n = 2 IP 3 3-kinase 54 V max = 5 µMs -1 , k a1 = 0.4 µM, n 1 = 4, k a2 = 10 µM, n 2 = 1 IP 3 5-phosphatase 44,103 V max = 1.25 s -1 PLC δ 44 V max = 0.02 µMs -1 , k a1 = 1 µM, n 1 = 2, k a2 = 1.5 µM…”

Geometric principles of second messenger dynamics in dendritic spines

“…It has been hypothesized that spatial and temporal separation of second messengers can be a powerful means of specifying signaling functions through the interplay of cell shape and biochemical regulators [3,4]. Therefore, an emerging concept in the understanding of signal transduction is that cell signaling is profoundly inhomogeneous in space, and that the spatio-temporal dynamics of signal molecules encode signaling specificity [5,6]. This concept has been approached both theoretically [4,7,8] and experimentally [9][10][11][12][13].…”

“…Dendritic spines have characteristic shapes and internal organization; a schematic of the mushroomlike morphology of mature spines is shown in Figure 1. A very thin neck (40 ∼ 200 nm in diameter and 0.08 ∼ 1.1 µm long) separates an actin-rich bulbous head (0.3 ∼ 1.5 µm in diameter) from the dendrite, suggesting that the spine head acts as an isolated signaling compartment [6,12,13,[34][35][36][37]. Additionally, roughly 14−19% of spines contain a distinct organelle called the spine apparatus (SA), which is a protrusion of the smooth endoplasmic reticulum (ER).…”