The endoplasmic reticulum as an integrating signalling organelle: from neuronal signalling to neuronal death

Abstract

The endoplasmic reticulum is one of the largest intracellular organelles represented by continuous network of cisternae and tubules, which occupies the substantial part of neuronal somatas and extends into finest neuronal processes. The endoplasmic reticulum controls protein synthesis as well as their post-translational processing, and generates variety of nucleus-targeted signals through Ca²⁺-binding chaperones. The normal functioning of the endoplasmic reticulum signalling cascades requires high concentrations of free calcium ions within the endoplasmic reticulum lumen ([Ca²⁺]_L), and severe alterations in [Ca²⁺]_L trigger endoplasmic reticulum stress response, manifested by either unfolded protein response (UPR) or endoplasmic reticulum overload response (EOR). At the same time, the endoplasmic reticulum is critically involved in fast neuronal signalling, by producing local or global cytosolic calcium signals via Ca²⁺-induced Ca²⁺ release (CICR) or inositol-1,4,5-trisphosphate-induced Ca²⁺ release (IICR). Both CICR and IICR are important for synaptic transmission and synaptic plasticity. Several special techniques allowing real-time [Ca²⁺]_L monitoring were developed recently. Video-imaging of [Ca²⁺]_L in neurones demonstrates that physiological signalling triggers minor decreases in overall intraluminal Ca²⁺ concentration due to strong activation of Ca²⁺ uptake, which prevents severe [Ca²⁺]_L alterations. The endoplasmic reticulum lumen also serves as a “tunnel” which allows rapid transport of Ca²⁺ ions within highly polarised nerve cells. Fluctuations of intraluminal free Ca²⁺ concentration represent a universal mechanism, which integrates physiological cellular signalling with protein synthesis and processing. In pathological conditions, fluctuations in [Ca²⁺]_L may initiate either adaptive or fatal stress responses.

Introduction

The endoplasmic reticulum is an intracellular organelle of fundamental importance present in all types of eucariotic cells. The endoplasmic reticulum is most likely the largest organelle, with endomembrane accounting for more than 50% of all the cellular membranes, and occupies a substantial part (>10%) of the cell volume. The endoplasmic reticulum lumen is densely packed with numerous enzymatic systems that allow protein synthesis in the rough endoplasmic reticulum and correct post-translational “folding” of these proteins. Any malfunctions in the latter process result in accumulation of unfolded proteins, which in turn activates several signalling systems aimed at appropriate compensatory responses. At the same time, the endoplasmic reticulum is recognised as an important component of a different signalling system, which is the cytosolic calcium signalling cascade. Within a framework of this cascade, the endoplasmic reticulum serves as a rapidly exchanging Ca²⁺ store, able to release Ca²⁺ ions upon appropriate physiological stimulation. In order for the endoplasmic reticulum to work as a dynamic Ca²⁺ store, a high concentration of free Ca²⁺ has to be maintained within its lumen, where [Ca²⁺] varies between 0.2 and 2 mM. Simultaneously, high intraluminal free Ca²⁺ concentration appears to be a key factor determining the activity of synthesis and processing of proteins within the endoplasmic reticulum, and disruption of endoplasmic reticulum Ca²⁺ homeostasis triggers endoplasmic reticulum stress response. When deficits of endoplasmic reticulum Ca²⁺ handling are severe and persisting, the endoplasmic reticulum becomes a source of cell death signals.

The Ca²⁺ ion emerges as a messenger molecule which integrates various signals within the endoplasmic reticulum: the fluctuations of [Ca²⁺]_L induced by signals originating at the level of the plasmalemma (i.e. Ca²⁺ entry or activation of metabotropic receptors) regulate in turn protein synthesis and processing via generating secondary signalling events between the endoplasmic reticulum and the nucleus. This view of the endoplasmic reticulum as a complex and universal signalling organelle is yet in statu nascendi (see e.g. Corbett and Michalak, 2000, Paschen and Frandsen, 2001); in this essay we shall focus on endoplasmic reticulum signalling functions in neurones. Several abbreviations used throughout the text are worth deciphering at this stage. The concentration of free Ca²⁺ within two compartments, the cytosol and the endoplasmic reticulum are abbreviated as [Ca²⁺]_i and [Ca²⁺]_L, respectively; SERCA stands for Sarco(Endo)plasmic Reticulum Calcium ATPase, InsP₃ for inositol-1,4,5-trisphosphate and grp stands for glucose-regulated protein.