Determining the Roles of Inositol Trisphosphate Receptors in Neurodegeneration: Interdisciplinary Perspectives on a Complex Topic (original) (raw)
Related papers
Cell Calcium, 2006
Presenilins (PS) are proteins involved in the pathogenesis of autosomal-dominant familial cases of Alzheimer's disease. Mutations in PS are known to induce specific alterations in cellular Ca 2+ signaling which might be involved in the pathogenesis of neurodegenerative diseases. Mouse embryonic fibroblasts (MEF) deficient in PS1 and PS2 (PS DKO) as well as the latter rescued with PS1 (Rescue), were used to investigate the underlying mechanism of these alterations in Ca 2+ signaling. PS DKO cells were characterized by a decrease in the [Ca 2+ ] ER as measured by ER-targeted aequorin luminescence and an increased level of type 1 inositol 1,4,5-trisphosphate receptor (IP 3 R1). The lower [Ca 2+ ] ER was associated with an increase in a Ca 2+ leak from the ER. The increased IP 3 R1 expression and the concomitant changes in ER Ca 2+ handling were reversed in the Rescue cells. Moreover using RNA-interference mediated reduction of IP 3 R1 we could demonstrate that the up-regulation of this isoform was responsible for the increased Ca 2+ leak and the lowered [Ca 2+ ] ER in PS DKO cells. Finally, we show that the decreased [Ca 2+ ] ER in PS DKO cells was protective against apoptosis.
Distinct Roles of Inositol 1,4,5-Trisphosphate Receptor Types 1 and 3 in Ca2+ Signaling
Journal of Biological Chemistry, 2004
Activation of the phospholipase C pathway by hormones, growth factors, and neurotransmitters results in generation of a second messenger inositol 1,4,5-trisphosphate (IP 3 ), 1 which diffuses to the cytoplasm and binds to an IP 3 receptor (IP 3 R), a Ca 2ϩ release channel on the endoplasmic reticulum (ER) (1). IP 3 R plays key roles in generation of spatially and temporally complex signaling patterns of cytosolic [Ca 2ϩ ] i , such as Ca 2ϩ oscillations. Since not only the amplitude but also the frequency of Ca 2ϩ oscillation is critical for activation of various downstream effectors (2-6), how IP 3 R contributes to these parameters is a key question in the vast area of cell biology.
Journal of Biological Chemistry, 2011
The type 1 inositol 1,4,5-trisphosphate receptor (InsP 3 R1) is a ubiquitous intracellular Ca 2؉ release channel that is vital to intracellular Ca 2؉ signaling. InsP 3 R1 is a proteolytic target of calpain, which cleaves the channel to form a 95-kDa carboxylterminal fragment that includes the transmembrane domains, which contain the ion pore. However, the functional consequences of calpain proteolysis on channel behavior and Ca 2؉ homeostasis are unknown. In the present study we have identified a unique calpain cleavage site in InsP 3 R1 and utilized a recombinant truncated form of the channel (capn-InsP 3 R1) corresponding to the stable, carboxyl-terminal fragment to examine the functional consequences of channel proteolysis. Single-channel recordings of capn-InsP 3 R1 revealed InsP 3-independent gating and high open probability (P o) under optimal cytoplasmic Ca 2؉ concentration ([Ca 2؉ ] i) conditions. However, some [Ca 2؉ ] i regulation of the cleaved channel remained, with a lower P o in suboptimal and inhibitory [Ca 2؉ ] i. Expression of capn-InsP 3 R1 in N2a cells reduced the Ca 2؉ content of ionomycin-releasable intracellular stores and decreased endoplasmic reticulum Ca 2؉ loading compared with control cells expressing full-length InsP 3 R1. Using a cleavage-specific antibody, we identified calpain-cleaved InsP 3 R1 in selectively vulnerable cerebellar Purkinje neurons after in vivo cardiac arrest. These findings indicate that calpain proteolysis of InsP 3 R1 generates a dysregulated channel that disrupts cellular Ca 2؉ homeostasis. Furthermore, our results demonstrate that calpain cleaves InsP 3 R1 in a clinically relevant injury model, suggesting that Ca 2؉ leak through the proteolyzed channel may act as a feedforward mechanism to enhance cell death. Changes in cytoplasmic free Ca 2ϩ concentration ([Ca 2ϩ ] i) act as a ubiquitous signaling system that is essential to proper neuronal function and survival. Conversely, disrupted [Ca 2ϩ ] i can serve as a trigger for cell death (1, 2). In particular, compelling evidence suggests that disruption of cellular Ca 2ϩ homeostasis, caused in part by dysfunction of Ca 2ϩ regulatory proteins, plays a causal role in both acute brain injury and chronic neurodegenerative diseases (3). The inositol 1,4,5-trisphosphate receptor (InsP 3 R), 2 a ubiquitous intracellular Ca 2ϩ release channel located on the endoplasmic reticulum (ER) membrane, may be an important component of the pathologic cascades leading to disrupted Ca 2ϩ homeostasis in many disease states. Cells deficient in InsP 3 Rs are resistant to apoptosis (4, 5) suggesting that InsP 3 R-mediated Ca 2ϩ signaling plays a mechanistic role in cell death. Altered InsP 3 R channel function induces aberrant neuronal Ca 2ϩ signaling in a variety of neurodegenerative diseases including Alzheimer disease (6, 7), Huntington disease (8), and ischemia (9). Observations in brain ischemia models also suggest altered InsP 3 R function, specifically, decreased InsP 3 binding (10, 11), decreased InsP 3-induced Ca 2ϩ release (12), and depletion of releasable Ca 2ϩ stores (13, 14). Proteolytic cleavage of InsP 3 R could explain these observations. The type 1 InsP 3 R (InsP 3 R1), the predominant neuronal isoform, is a substrate for both the caspase and calpain families of cysteine proteases (15). These proteases are indirectly (caspase-3) and directly (calpain) activated by Ca 2ϩ and are known to play a central role in apoptotic and necrotic cell death pathways (16). Proteolytic activity of these enzymes is limited and site-specific, typically altering rather than eliminating substrate function. In the case of Ca 2ϩ regulatory proteins, this may initiate a positive feedback loop that further increases protease activation via increases in [Ca 2ϩ ] i. Caspase-3 or calpain cleavage of InsP 3 R1 generates carboxylterminal fragments of ϳ95 kDa (17). Caspase-3 cleaves InsP 3 R1 at a highly conserved DEVD consensus sequence within the coupling domain (17) (Fig. 1A). Caspase-mediated proteolysis of the channel has been observed in several models of apoptosis (17-19). Previous studies have demonstrated altered ER Ca 2ϩ homeostasis in cell lines expressing a recombinant caspase-derived carboxyl-terminal fragment of InsP 3 R1, suggesting that cleavage generates an unregulated channel that may leak Ca 2ϩ
Intracellular calcium channels: Inositol-1,4,5-trisphosphate receptors
European Journal of Pharmacology, 2014
The inositol-1,4,5-trisphosphate receptors (InsP 3 Rs) are the major intracellular Ca 2+-release channels in cells. Activity of InsP 3 Rs is essential for elementary and global Ca 2+ events in the cell. There are three InsP 3 Rs isoforms that are present in mammalian cells. In this review review we will focus primarily on InsP 3 R type 1. The InsP 3 R1 is a predominant isoform in neurons and it is most extensively studied isoform. Combination of biophysical and structural methods revealed key mechanisms of InsP 3 R function and modulation. Cell biological and biochemical studies lead to identification of a large number of InsP 3 R-binding proteins. InsP 3 Rs are involved in the regulation of numerous physiological processes, including learning and memory, proliferation, differentiation, development and cell death. Malfunction of InsP 3 R1 play a role in a number of neurodegenerative disorders and other disease states. InsP 3 Rs represent a potentially valuable drug target for treatment of these disorders and for modulating activity of neurons and other cells. Future studies will provide better understanding of physiological functions of InsP 3 Rs in health and disease.
The Cerebellum, 2011
The inositol 1,4,5-trisphosphate (IP 3 ) receptor is highly expressed in cerebellar Purkinje cells and mediates conspicuous calcium release from intracellular calcium stores. Receptor stimulation, such as through mGluR1, activates the G q -PLC pathway, which leads to IP 3 -induced calcium release and subsequent cellular responses, including cerebellar long-term depression in Purkinje cells. Recent studies have demonstrated the regulatory mechanisms of IP 3 receptor, revealing activation via IP 3 and Ca 2+ , inactivation via high concentrations of Ca 2+ , and modulation by various proteins that bind to the IP 3 receptor. Novel calcium imaging techniques and caged compounds provide analysis of calcium signals at the single spine level in relation to the induction of long-term depression. Genetically encoded indicators for calcium or IP 3 could provide alternate Ca 2+ or IP 3 imaging, in particular, for in vivo observations. IP 3 -induced calcium release participates in early development of dendritic branch formation, and lossof-function mutations or hyper-activation could result various diseases. The IP 3 receptor plays a central role in calcium signaling in Purkinje cells, affecting a wide variety of cellular functions, including development, plasticity, maintenance of synaptic functions, and cerebellar motor control.
Regulatory Mechanisms of Endoplasmic Reticulum Resident IP3 Receptors
Dysregulated calcium signaling and accumulation of aberrant proteins causing endoplasmic reticulum stress are the early sign of intra-axonal pathological events in many neurodegenerative diseases, and apoptotic signaling is initiated when the stress goes beyond the maximum threshold level of endoplasmic reticulum. The fate of the cell to undergo apoptosis is controlled by Ca2 + signaling and dynamics at the level of the endoplasmic reticulum. Endoplasmic reticu-lum resident inositol 1,4,5-trisphosphate receptors (IP3R) play a pivotal role in cell death signaling by mediating Ca2 + flux from the endoplasmic reticulum into the cytosol and mito-chondria. Hence, many prosurvival and prodeath signaling pathways and proteins affect Ca2 + signaling by directly targeting IP3R channels, which can happen in an IP3R-isoform-dependent manner. Here, in this review, we summarize the regulatory mechanisms of inositol triphosphate receptors in calcium regulation and initiation of apoptosis during unfolded protein response.