Understand the Regulation of Learning and Memory Formation from a Molecular Prospective

BPJ_112_6.c1.inddWhen most people talk about calcium (Ca2+), they think about building bones and muscle contraction. In fact, calcium is also essential for learning and memory formation. Molecular basis for learning and memory formation has aroused attention since 1980s.  So what does calcium do with learning and memory formation? The calcium-modulating protein calmodulin (CaM) coordinates the activation of a family of Ca2+-regulated proteins, which are crucial for synaptic plasticity associated with learning and memory in neurons. These proteins include neurogranin (Ng) and CaM-dependent kinase II (CaMKII). In a resting cell, CaM is mostly reserved by Ng and free of Ca2+, whereas in a stimulated cell, CaM is able to bind Ca2+ and activate CaMII, which plays a pivotal role in learning and memory formation for both long-term potentiation and mechanisms for the modulation of synaptic efficacy.

The cover image for the March 28 issue of the Biophysical Journal shows the crystal structure of CaM-CaMKII peptide and the structure of CaM-Ng from coarse-grained molecular simulations. CaM molecules are ribbons in silver, calcium ions are represented by yellow beads, CaMKII peptide is in green surface representation, and Ng peptide is in red surface representation. One CaM-Ng peptide complex is near, where the Ng is aligned with a “pry” (pink); the other is far, indicating rich level of Ng. The images were rendered using the software Visual Molecular Dynamics developed by University of Illinois at Urbana-Champaign with the built-in Tachyon ray tracer. The illustration of a neuron in hippocampus is taken from Shelley Halpain, UC San Diego. Dendrites are green, dendritic spines red, and DNA (in cell nucleus) blue. The illustration of a human brain contains red dots to indicate active parts of the cerebral cortex.

Our computational study provides the very first detailed description at atomistic level ofhow binding of CaM with two distinct targets, Ng and CaMKII, influences the release of Ca2+ from CaM, as a molecular underpinning of CaM-dependent Ca2+ signaling in neurons. We believe this study bridges the molecular regulations in atomistic detail and the understanding of cellular process cascade of learning and memory formation.

– Pengzhi Zhang, Swarnendu Tripathi, Hoa Trinh, Margaret S. Cheung

Calcium Release Sparks Our Interest

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The cover of Biophysical Journal (Volume 107, Issue 12) depicts a calcium “spark” occurring at a calcium release site in the cardiac myocyte. This is where calcium ions are released out of the sarcoplasmic reticulum through a cluster of release channels. The cell-wide calcium release comprises thousands of such spark events, which occur when the cell is electrically stimulated, thus leading to contraction. Sparks can also occur spontaneously and play an important role in myocyte physiology by contributing to calcium leak out of the sarcoplasmic reticulum. Furthermore, sparks can initiate cellular arrhythmias under pathological conditions. We used the model to show how changes to release channel regulation, membrane geometry, and release channel cluster structure, as observed in heart disease, alters calcium release and the occurrence of sparks.

Our model geometry was imported into the 3D rendering software Blender. We applied a translucent effect to the junctional sarcoplasmic reticulum to expose a packed cluster of green release channels. The structure of this cluster was determined using superresolution STED microscopy. The sparks, representing calcium ions, illuminate the scene; their positions and directions are determined by a simulation of a particle system subject to Brownian motion.

Our work is motivated by the desire to understand the molecular events leading to cardiac arrhythmias. Aberrant calcium release at these sites can lead to altered cell physiology and predispose the cell to arrhythmia-inducing afterdepolarizations. We used the model to predict the effects of cell structure remodeling, as observed in heart failure and catecholaminergic polymorphic ventricular tachycardia (CPVT). Improving our understanding of the calcium release process will help us advance therapies for these and other diseases.

Importantly, we have made this model available as a cloud-based service using the Galaxy research platform. Example simulation histories and workflows that produce the data featured in the article are available under Shared Data. Users may also customize the model, run simulations on cloud-based computing resources, and analyze the output through their web browser. The Galaxy server is available at: http://cvrg.galaxycloud.org/.

– Mark A. Walker, George S. B. Williams,  Tobias Kohl, Stephan E. Lehnart, M. Saleet Jafri, Joseph L. Greenstein, W. J. Lederer, Raimond L. Winslow