Activity-dependent calcium signaling and ERK-MAP kinases in neurons: A link to structural plasticity of the nucleus and gene transcription regulation

Abstract

Activity-dependent gene expression is important for the formation and maturation of neuronal networks, neuronal survival and for plastic modifications within mature networks. At the level of individual neurons, expression of new protein is required for dendritic branching, synapse formation and elimination. Experience-driven synaptic activity induces membrane depolarization, which in turn evokes intracellular calcium transients that are decoded according to their source and strength by intracellular calcium sensing proteins. In order to activate the gene transcription machinery of the cell, calcium signals have to be conveyed from the site of their generation in the cytoplasm to the cell nucleus. This can occur via a variety of mechanisms and with different kinetics depending on the source and amplitude of calcium influx. One mechanism involves the propagation of calcium itself, leading to nuclear calcium transients that subsequently activate transcription. The mitogen-activated protein kinase (MAPK) cascade represents a second central signaling module that transduces information from the site of calcium signal generation at the plasma membrane to the nucleus. Nuclear signaling of the MAPK cascades catalyzes the phosphorylation of transcription factors but also regulates gene transcription more globally at the level of chromatin remodeling as well as through its recently identified role in the modulation of nuclear shape. Here we discuss the possible mechanisms by which the MAPKs ERK1 and ERK2, activated by synaptically evoked calcium influx, can signal to the nucleus and regulate gene transcription. Moreover, we describe how MAPK-dependent structural plasticity of the nuclear envelope enhances nuclear calcium signaling and suggest possible implications for the regulation of gene transcription in the context of nuclear geometry.

Introduction

Individual neurons are born within the first weeks of life and persist throughout the lifetime of the animal, which can for some species exceed 100 years. During this time the cell has to undergo many experience-driven adaptations, which are reflected by remodeling of the dendritic tree, axonal growth and formation and elimination of synapses [1], [2], [3], [4], [5], [6], [7]. Such processes are controlled by electrical activity and require transcription of appropriate sets of genes in the nucleus [7], [8]. The major intracellular messenger that transduces electrical activity into gene expression is calcium [9], [10]. During development, the maturation of excitatory synapses depends on calcium influx through synaptic N-methyl-d-aspartate receptors (NMDARs) which leads to local modifications such as insertion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) into the spine and rearrangement of the post synaptic density (PSD) [11], [12]. Moreover, activity-dependent calcium-influx through NMDARs and voltage-gated calcium channels (VGCCs) is required to induce gene transcription events in the nucleus, which underlie widespread loss or pruning of dendritic spines and large-scale reorganization of the dendritic tree [13], [14].

LTP and LTD are considered cellular correlates of learning and memory and involve rapid and persistent remodeling of synaptic connections. Rapid processes such as AMPAR insertion/removal, remodeling of the actin cytoskeleton and spine turnover are regulated by local calcium and its downstream kinases and are thought to be independent of gene transcription and nuclear calcium signaling [15]. Long-lasting adaptations however, require synthesis of new proteins that alter neuronal function and stabilize synapses at a longer time scale [7], [8], [16], [17]. In order to decode the requirements of the synapse at the level of gene transcription, reliable delivery of the information about synaptic activity to the nucleus is essential. In principle, two strategies exist by which calcium can transform electrical activity into a nuclear gene transcription event: (1) calcium activates signaling molecules in the cytoplasm which carry the information to the nucleus via direct nuclear translocation or indirectly via signaling cascades, or (2) calcium itself crosses the nuclear envelope and acts directly within the cell nucleus.

In recent years many different calcium-dependent signaling pathways to the nucleus and their role in encoding the source and kinetics of intracellular calcium transients have been described [7], [18], [19], [20], [21]. Since calcium-dependent activation of gene-transcription eventually requires the physical translocation of a signal from the cytoplasm across the nuclear envelope it is important to consider the accessibility of the nucleus for such signaling molecules. Small molecules such as calcium or calcium bound to calmodulin may enter the nucleus unhindered via diffusion through nuclear pore complexes [22], [23], [24], [25]. However, larger molecules such as the calcium/calmodulin dependent kinases (CaMKs), protein kinase A (PKA) or the extracellular signal-regulated kinases 1 and 2 (ERK1/2) exceed the size limit for passive diffusion through the pore and thus require a mechanism that facilitates their nuclear translocation [26], [27], [28], [29]. In the first part of this review we will consider the principal mechanisms by which calcium signals can be conveyed to the nucleus focusing on nuclear entry of calcium and on nuclear signaling of the ERK1/2-MAPK cascade.

In addition to direct activation of transcription factors recent evidence suggests that ERK1/2 can regulate chromatin remodeling – a higher-order mechanism of transcriptional regulation. ERK1/2-dependent phosphorylation of histone H3 and subsequent gene transcription have been described in many cell types and more recently these processes have been demonstrated to be important for synaptic plasticity and memory formation in different areas of the brain. Finally, recent evidence suggests that calcium and ERK1/2 act in concert at the level of structural remodeling of the nuclear envelope itself. Synaptic activity initiates deep infoldings of the nuclear membrane leading to a compartmentalized nucleoplasm, an increased surface area and amplified nuclear calcium signaling. In the second part of this review, we will summarize the current knowledge about neuronal ERK1/2 signaling and discuss the new nuclear functions of ERK1/2 in more detail. Moreover, we will provide suggestions how structural plasticity of the nucleus can impact on nuclear calcium signaling and activity-dependent gene transcription.