Electrotonic Signals along Intracellular Membranes May Interconnect Dendritic Spines and Nucleus

Shemer, Itzhak; Brinne, Björn; Tegnér, Jesper; Grillner, Sten

doi:10.1371/journal.pcbi.1000036

Cited by 20 publications

(19 citation statements)

References 64 publications

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“…Our modeling emphasizes that Ca 2+ waves can have large variability in speed and distance of propagation, which will have major effects on how Ca 2+ is distributed and which targets are hit at what concentrations. However, we note that an entirely different role for ER has been proposed by Shemer et al (2008). Instead of a role for ER in enhancing Ca 2+ waves, they suggested that the ER forms a “cable-within-a-cable” which is electrically active and would provide more rapid distal to proximal communication via electrical signaling comparable to that of the plasma membrane.…”

Section: Discussionmentioning

confidence: 72%

Neuronal Calcium Wave Propagation Varies with Changes in Endoplasmic Reticulum Parameters: A Computer Model

et al. 2015

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Calcium (Ca2+) waves provide a complement to neuronal electrical signaling, forming a key part of a neuron’s second messenger system. We developed a reaction-diffusion model of an apical dendrite with diffusible inositol triphosphate (IP3), diffusible Ca2+, IP3 receptors (IP3Rs), endoplasmic reticulum (ER) Ca2+ leak, and ER pump (SERCA) on ER. Ca2+ is released from ER stores via IP3Rs upon binding of IP3 and Ca2+. This results in Ca2+-induced-Ca2+-release (CICR) and increases Ca2+ spread. At least two modes of Ca2+ wave spread have been suggested: a continuous mode based on presumed relative homogeneity of ER within the cell; and a pseudo-saltatory model where Ca2+ regeneration occurs at discrete points with diffusion between them. We compared the effects of three patterns of hypothesized IP3R distribution: 1. continuous homogeneous ER, 2. hotspots with increased IP3R density (IP3R hotspots), 3. areas of increased ER density (ER stacks). All three modes produced Ca2+ waves with velocities similar to those measured in vitro (~50–90µm /sec). Continuous ER showed high sensitivity to IP3R density increases, with time to onset reduced and speed increased. Increases in SERCA density resulted in opposite effects. The measures were sensitive to changes in density and spacing of IP3R hotspots and stacks. Increasing the apparent diffusion coefficient of Ca2+ substantially increased wave speed. An extended electrochemical model, including voltage gated calcium channels and AMPA synapses, demonstrated that membrane priming via AMPA stimulation enhances subsequent Ca2+ wave amplitude and duration. Our modeling suggests that pharmacological targeting of IP3Rs and SERCA could allow modulation of Ca2+ wave propagation in diseases where Ca2+ dysregulation has been implicated.

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Section: Discussionmentioning

confidence: 72%

Neuronal Calcium Wave Propagation Varies with Changes in Endoplasmic Reticulum Parameters: A Computer Model

et al. 2015

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“…Calcium in cytosol comes from the extracellular space, modeled here as an inexhaustible source, and from organelles which are exhaustible. Compared to mitochondria, ER is likely to be a more accessible Ca 2+ source across multiple locations including spines – it spreads diffusely throughout the neuron, foliating at key points to provide additional surface area (Shemer et al, 2008, Berridge, 1998). …”

Section: Discussionmentioning

confidence: 99%

Calcium regulation of HCN channels supports persistent activity in a multiscale model of neocortex

et al. 2016

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Neuronal persistent activity has been primarily assessed in terms of electrical mechanisms, without attention to the complex array of molecular events that also control cell excitability. We developed a multiscale neocortical model proceeding from the molecular to the network level to assess the contributions of calcium regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in providing additional and complementary support of continuing activation in the network. The network contained 776 compartmental neurons arranged in the cortical layers, connected using synapses containing AMPA/NMDA/GABAA/GABAB receptors. Metabotropic glutamate receptors (mGluR) produced inositol triphosphate (IP3) which caused release of Ca2+ from endoplasmic reticulum (ER) stores, with reuptake by sarco/ER Ca2+-ATP-ase pumps (SERCA), and influence on HCN channels. Stimulus-induced depolarization led to Ca2+ influx via NMDA and voltage-gated Ca2+ channels (VGCCs). After a delay, mGluR activation led to ER Ca2+ release via IP3 receptors. These factors increased HCN channel conductance and produced firing lasting for ~1 minute. The model displayed inter-scale synergies among synaptic weights, excitation/inhibition balance, firing rates, membrane depolarization, calcium levels, regulation of HCN channels, and induction of persistent activity. The interaction between inhibition and Ca2+ at the HCN channel nexus determined a limited range of inhibition strengths for which intracellular Ca2+ could prepare population-specific persistent activity. Interactions between metabotropic and ionotropic inputs to the neuron demonstrated how multiple pathways could contribute in a complementary manner to persistent activity. Such redundancy and complementarity via multiple pathways is a critical feature of biological systems. Mediation of activation at different time scales, and through different pathways, would be expected to protect against disruption, in this case providing stability for persistent activity.

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“…3D) (Shemer et al 2008). This proposal is grounded on the basis that, like the plasma membrane, the ER membrane is an effective charge separator and may thus support the generation and propagation of trans-ER depolarizations and hyperpolarizations.…”

Section: The Endoplasmic Reticulum As a Conduit From Synapse To Nucleusmentioning

confidence: 99%

“…An additional means by which synaptic activity could be conveyed to the nucleus involves the passive propagation of electrical potentials along ER membranes to the nuclear envelope ( Fig. 3D) (Shemer et al 2008).…”

Section: Local Ca 2þ Signaling Has Global Functional Consequencesmentioning

confidence: 99%

“…Using a computational "cable in cable" model, it was shown that electrotonic potentials across the ER-and associated current flow within the ER-can be rapidly and effectively transmitted both from synapse to soma, and from the soma into the dendritic arbor (Shemer et al 2008). Significantly, the investigators observe that these two modes of signal propagation have opposite effects on the transmembrane potential across the nuclear envelope and suggest on this basis that electrotonic signal propagation along ER membranes may account for the ability of the nucleus to differentiate between synaptic signals originating at dendritic spines and backpropagating action potentials generated in the soma (Shemer et al 2008). That said, it remains to be determined what the specific consequences of nuclear envelope depolarizations or hyperpolarizations might be.…”

Section: The Endoplasmic Reticulum As a Conduit From Synapse To Nucleusmentioning

confidence: 99%

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Calcium Signaling in Synapse-to-Nucleus Communication

Hagenston

Bading

2011

Cold Spring Harbor Perspectives in Biology

123

113

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Changes in the intracellular concentration of calcium ions in neurons are involved in neurite growth, development, and remodeling, regulation of neuronal excitability, increases and decreases in the strength of synaptic connections, and the activation of survival and programmed cell death pathways. An important aspect of the signals that trigger these processes is that they are frequently initiated in the form of glutamatergic neurotransmission within dendritic trees, while their completion involves specific changes in the patterns of genes expressed within neuronal nuclei. Accordingly, two prominent aims of research concerned with calcium signaling in neurons are determination of the mechanisms governing information conveyance between synapse and nucleus, and discovery of the rules dictating translation of specific patterns of inputs into appropriate and specific transcriptional responses. In this article, we present an overview of the avenues by which glutamatergic excitation of dendrites may be communicated to the neuronal nucleus and the primary calcium-dependent signaling pathways by which synaptic activity can invoke changes in neuronal gene expression programs.

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Electrotonic Signals along Intracellular Membranes May Interconnect Dendritic Spines and Nucleus

Cited by 20 publications

References 64 publications

Neuronal Calcium Wave Propagation Varies with Changes in Endoplasmic Reticulum Parameters: A Computer Model

Neuronal Calcium Wave Propagation Varies with Changes in Endoplasmic Reticulum Parameters: A Computer Model

Calcium regulation of HCN channels supports persistent activity in a multiscale model of neocortex

Calcium Signaling in Synapse-to-Nucleus Communication

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