Role of Endoplasmic Reticulum-Mediated Ca 2+ Signaling in Neuronal Cell Death

Abstract

Significance:

Properly controlled intracellular Ca²⁺ dynamics is crucial for regulation of neuronal function and survival in the central nervous system. The endoplasmic reticulum (ER), a major intracellular Ca²⁺ store, plays a critical role as a source and sink for neuronal Ca²⁺.

Recent Advances:

Accumulating evidence indicates that disrupted ER Ca²⁺ signaling is involved in neuronal cell death under various pathological conditions, providing novel insight into neurodegenerative disease mechanisms.

Critical Issues:

We summarize current knowledge concerning the relationship between abnormal ER Ca²⁺ dynamics and neuronal cell death. We also introduce recent technical advances for probing ER intraluminal Ca²⁺ dynamics with unprecedented spatiotemporal resolution.

Future Directions:

Further studies on ER Ca²⁺ signaling are expected to provide progress for unmet medical needs in neurodegenerative disease. Antioxid. Redox Signal. 29, 1147–1157.

Introduction

Intracellular Ca ²⁺ is a major second messenger regulating multifarious functions in most, if not all, cell types, including neurons of the central nervous system (CNS) (6). Neuronal intracellular Ca²⁺ concentrations ([Ca²⁺]_i) are regulated not only by Ca²⁺ influx from extracellular fluid via ligand- and voltage-gated Ca²⁺ channels (VGCCs) but also by Ca²⁺ release and uptake in the endoplasmic reticulum (ER). Properly controlled [Ca²⁺]_i is crucial for neuronal function and survival. Cellular overloading of Ca²⁺ induced by excessive activity-dependent Ca²⁺ influx is thought to be a major cause of excitotoxic neuronal cell death. Furthermore, dysregulation of ER-mediated Ca²⁺ signaling is also involved in neuronal cell death under various pathological conditions (9, 109, 124). Therefore, studies on disrupted ER Ca²⁺ dynamics may provide novel insight into disease mechanisms and also lead to identification of novel therapeutic targets.

In the present review, we summarize current knowledge concerning the relationship between ER Ca²⁺ dynamics and neuronal cell death. We then discuss the use of recently developed genetically encoded ER Ca²⁺ indicators (114) to further understand the role of ER Ca²⁺ dynamics in neuronal cell death.

Neuronal ER Ca²⁺ Signaling

The ER plays a key role in not only protein synthesis and transport but also as a Ca²⁺ source and sink for influencing intracellular Ca²⁺ signals (6, 124). High concentrations of Ca²⁺ and Ca²⁺-binding proteins within the ER lumen render the organelle a large-capacity Ca²⁺ reservoir (96). Intraluminal free Ca²⁺ concentration within the ER ([Ca²⁺]_ER) reaches the millimolar range, which is far higher than nano- to micromolar ranges of cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) (115). This large concentration gradient across the ER membrane is a driving force for Ca²⁺ release from the ER to the cytosol. In neurons, fine tubular ER networks extend throughout cellular compartments, including dendritic spines (40, 72, 107), allowing involvement of ER Ca²⁺ signaling in multifarious functions, including synaptic plasticity and synaptic maintenance (4, 33, 61, 91). Proper regulation of Ca²⁺ release channels and pumps in the ER membrane is crucial for normal ER Ca²⁺ signaling.

Two types of Ca²⁺ release channels (inositol 1,4,5-trisphosphate [IP₃] receptors [IP₃Rs] and ryanodine receptors [RyRs]) mediate Ca²⁺ mobilization from the ER. A wide variety of neurotransmitter or neurotrophin receptors mediate IP₃ generation through G_q-coupled activation of phospholipase Cβ or tyrosine kinase-mediated activation of phospholipase Cγ (8) (Fig. 1). IP₃ is not the sole ligand of IP₃R, but cooperative activation with Ca²⁺ is required for channel opening (11, 47) (Fig. 1). Among three mammalian subtypes of IP₃R (IP₃R1, 2, and 3), IP₃R1 is the major subtype expressed in CNS neurons (27, 32).

FIG. 1.

Neuronal ER Ca²⁺ signaling. Schematic diagram of ER Ca²⁺ signaling mediated by Ca²⁺ channels and pumps in the ER and plasma membrane. CALHM1, calcium homeostasis modulator 1; ER, endoplasmic reticulum; GPCR, G-protein-coupled receptor; IP₃, inositol 1,4,5-trisphosphate; IP₃R, IP₃ receptor; NMDAR, N-methyl-D-aspartate receptor; nNOS, neuronal-type nitric oxide synthase; PLCβ, phospholipase Cβ; PLCγ, phospholipase Cγ; PS, presenilins; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; RyR, ryanodine receptor; SERCA, sarco-ER Ca²⁺ ATPase; STIM, stromal interaction molecule; VGCC, voltage-gated Ca²⁺ channel.

RyR is a Ca²⁺ release channel activated by Ca²⁺, and which mediates Ca²⁺-induced Ca²⁺ release (CICR). Thus, Ca²⁺ influx via VGCC or ligand-gated channels, including the N-methyl-D-aspartate receptor, triggers neuronal CICR and subsequent Ca²⁺-dependent events (25, 26, 54) (Fig. 1). Three mammalian subtypes of RyR (RyR1, 2, and 3) are expressed throughout the brain with relatively minor differences in expression pattern (81). It has been postulated that there are intrinsic modulators of RyR opening, such as cyclic ADP-ribose (77), although their significance is debated (31, 105). Reactive oxygen species are also known as a critical modulator of RyR (2, 71, 75, 121) (Fig. 1). Furthermore, nitric oxide (NO)-induced activation of RyR1 is involved in neuronal Ca²⁺ signaling and cell death (51, 78) (Fig. 1).

High levels of [Ca²⁺]_ER are maintained by sarco-ER Ca²⁺ ATPase (SERCA) pumps. SERCA transports Ca²⁺ from the cytosol to the ER lumen against a large concentration gradient by hydrolyzing ATP (92) (Fig. 1). SERCA is crucial for Ca²⁺ refilling into the ER after Ca²⁺ release via IP₃R or RyR. Treatment with an SERCA inhibitor such as thapsigargin and cyclopiazonic acid effectively depletes Ca²⁺ from the ER, suggesting that basal SERCA activity is required to counteract basal Ca²⁺ leakage from the ER. SERCA activity is regulated by ER-resident transmembrane proteins, including phospholamban, sarcolipin, myoregulin, endoregulin, and another regulin (1, 60, 69). The SERCA pump includes three gene products, SERCA1, SERCA2, and SERCA3. Two isoforms of SERCA2 (SERCA2a and 2b) as well as SERCA3 are expressed in the CNS (3, 124).

The ER is also involved in an active Ca²⁺ refilling mechanism that is evoked in response to ER Ca²⁺ depletion. Decreased [Ca²⁺]_ER induces Ca²⁺ influx across the plasma membrane. This event, called store-operated Ca²⁺ entry (SOCE), enhances ER replenishment via SERCA-dependent Ca²⁺ uptake (Fig. 1). SOCE is mainly mediated by the ER-plasma membrane interaction via stromal interaction molecule (STIM) proteins in the ER membrane and Orai channels in the plasma membrane (67, 97, 126) (Fig. 1). Two subtypes of STIM (STIM1 and 2) localized within the ER membrane sense [Ca²⁺]_ER via their intraluminal domain and multimerize on decreased [Ca²⁺]_ER to activate Orai channels in the plasma membrane via an interaction between the cytosolic domains of STIM and Orai molecules (106). Neurons show active Ca²⁺ influx via VGCC and ligand-gated channels, in turn enhancing ER Ca²⁺ filling (14, 28, 29, 35, 41, 44, 95, 108). However, STIM-dependent ER Ca²⁺ filling is also crucial to maintain ER Ca²⁺ content in neurons (41, 113).

Disrupted Ca²⁺ Loading in the ER and Neuronal Cell Death

Under physiological states, [Ca²⁺]_ER is maintained within a certain range by the balance between Ca²⁺ uptake and release. Disruption in ER Ca²⁺ loading state (i.e., depletion or overloading of Ca²⁺) may lead to pathological reactions (Fig. 2). It has been established that [Ca²⁺]_ER depletion inhibits the protein folding mechanism and induces the unfolded protein response, which is followed by apoptotic cell death (22). Depletion of Ca²⁺ within the ER and the resulting ER stress response are implicated in ischemia/reperfusion-induced neuronal death (22, 23, 58, 76, 90). Although the precise mechanism remains elusive, NO-dependent processes are, at least in part, involved in ischemia/reperfusion-induced ER Ca²⁺ depletion (16, 23, 51, 58) (Figs. 2 and 3).

FIG. 2.

Dysregulation of neuronal ER Ca²⁺ signaling and neurodegenerative disease. Schematic diagram showing the relationship between disrupted ER Ca²⁺ signaling components and neurodegenerative disease. IP₃R1, type 1 IP₃R; Htt, huntingtin.

FIG. 3.

NO-induced brain injury due to stroke involves RyRs. Ischemia/reperfusion-induced brain injury was evaluated by triphenyl tetrazolium chloride staining of brain slices 24 h after transient MCAO. The infarct area (white colored area in each slice) was reduced in NO synthase 1 (Nos1)^−/− mice compared with Nos1 ^+/+ mice. Administration of dantrolene (Dan), RyR inhibitor, exerted a protective effect against MCAO-induced damage in Nos1 ^+/+ mice, whereas no further protection was observed in Nos1 ^−/− mice. Therefore, NOS1-dependent production of NO and resulting activation of RyR are crucial for the induction of brain injury on stroke. Modified from Kakizawa et al. (51). MCAO, middle cerebral artery occlusion; NO, nitric oxide; NOS1, neuronal-type nitric oxide synthase.

Sustained disruption of intracellular Ca²⁺ homeostasis involving imbalanced ER Ca²⁺ loading states (namely, the Ca²⁺ hypothesis) has been postulated as a critical factor in the etiology of Alzheimer's disease (AD) (7, 10, 17, 62). Presenilins (PS) are the catalytic component of γ-secretase complexes, which cleave amyloid precursor protein to produce amyloid-β. Mutations in PS are linked to some forms of familial AD (FAD), and thus, PS are recognized as critical players in the amyloid hypothesis (46, 101). In contrast, a crucial role for PS in the Ca²⁺ hypothesis has been documented. Neuronal attenuation of SOCE is one of the hallmark phenotypes of FAD-linked PS mutations (65, 127). Attenuation of SOCE, involving downregulation of STIM1 and STIM2, induces destabilization of dendritic spine morphology in hippocampal neurons (113, 122, 130), which may lead to disrupted synaptic functions underlying memory and cognitive deficits in AD. Prolonged disruption of synaptic functions is likely to provoke neurodegeneration (30).

Excessive ER Ca²⁺ loading is proposed as a cause of attenuated SOCE in FAD-linked PS mutations (65). In line with this hypothesis, PS can form putative Ca²⁺ leak channels on the ER membrane, and FAD-linked mutations in PS cause disruption of Ca²⁺ leakage from the ER, resulting in excessive ER Ca²⁺ loading (123) [Fig. 2, but see also Shilling et al. (103)]. It has also been reported that SERCA activity is enhanced by PS1, and that an FAD-linked PS1 mutant has a greater SERCA enhancing effect than wild-type PS1, which may lead to excessive ER Ca²⁺ loading (37). While excessive ER Ca²⁺ loading is associated with FAD-linked PS mutations in the above studies, it should be noted that unchanged or even decreased ER Ca²⁺ loading by PS mutants has also been reported (15, 20, 74, 128).

The calcium homeostasis modulator 1 (CALHM1) is another protein of interest in the Ca²⁺ hypothesis of AD. CALHM1 is localized in both the plasma membrane and ER membrane, and has been shown to form a Ca²⁺ leak channel in the plasma membrane (24). CALHM1 may also function as a Ca²⁺ leak channel in the ER, as overexpression of CALHM1 reduces ER Ca²⁺ content (34). Similarly, a polymorphism in the CALHM1 gene reduces Ca²⁺ permeability and also increases amyloid-β levels and is thereby linked to AD risk (24, 59, 80, 99). Therefore, it is possible that CALHM1 mutation disrupts ER Ca²⁺ leakage and results in excessive ER Ca²⁺ loading in the same manner as PS mutations (Fig. 2).

Disrupted Ca²⁺ Release and Neurodegeneration

The relationship between disrupted Ca²⁺ release function and neurodegenerative disease has been reported. Excessive or attenuated Ca²⁺ release via IP₃R and RyR is implicated in several neurodegenerative diseases (Table 1 and Fig. 2).

Table 1.

Deranged Ca²⁺ Release Activity Via IP₃R and RyR Implicated in Neurodegenerative Diseases

	IP₃R			RyR
	Subtype	Deranged activity	Ref.	Subtype	Deranged activity	Ref.
FAD	1	Excessive	(20, 21, 104)	3	Excessive	(18)
FAD	1	Excessive	(20, 21, 104)	Unspecified	Excessive	(100, 110)
HD	1	Excessive	(119, 120, 129)	1	Excessive	(116)
HD	1	Attenuated	(43)	1	Excessive	(116)
SCA2	1	Excessive	(55, 68)
SCA3	1	Excessive	(19)	Unspecified	Excessive	(19)
SCA15	1	Attenuated	(39, 57, 64)

FAD, familial Alzheimer's disease; HD, Huntington's disease; IP₃R, inositol 1,4,5-trisphosphate receptor; RyR, ryanodine receptor; SCA, spinocerebellar ataxia.

Increased activity and/or expression of IP₃R (20, 21, 104) and RyR (18, 100, 110) have been observed in cells expressing PS with FAD-linked mutations. Exaggerated Ca²⁺ release is expected to exacerbate Ca²⁺-dependent mechanisms involved in AD pathogenesis (82). Enhanced IP₃R and RyR function in cooperation with excessive ER Ca²⁺ loading (associated with FAD-linked PS mutations) may further exaggerate Ca²⁺ release from the ER.

Huntington's disease (HD) is an autosomal dominant genetic disorder that is caused by CAG triplet (CAG repeat) expansion in the huntingtin (Htt) gene (38). Insertion of polyglutamines coded by CAG repeats changes the properties of Htt protein allowing toxic interactions with various target molecules (52), for example, mutant Htt protein directly binds to IP₃R1 (120) (Fig. 2). This interaction increases the affinity of IP₃R1 for IP₃ and enhances Ca²⁺ release from the ER (120), which has been suggested to induce Ca²⁺ overloading in mitochondria and trigger apoptosis of striatal neurons (119, 129). Not only the enhancement but the impairment of IP₃R1 function is also implicated in HD. The impairment of IP₃R1-mediated Ca²⁺ release due to the reduced interaction between IP₃R1 and GRP78, an ER chaperone, is reported in striatal neurons of HD model mice (43). The involvement of RyR is also reported. The enhanced spontaneous Ca²⁺ release (Ca²⁺ leak) via RyR is implicated in neuronal cell death induced by mutant Htt (116).

Spinocerebellar ataxias (SCAs) are genetic disorders caused by either a recessive or dominant gene. SCA2 is caused by CAG repeat expansion in the ataxin-2 gene, and results in cerebellar Purkinje cell (PC) degeneration (38). Mutant ataxin-2 protein binds to IP₃R1, increasing the affinity of IP₃R1 for IP₃ and enhancing IP₃-induced Ca²⁺ release (55, 68) (Fig. 2). The effect is similar to that of mutant Htt protein described above. IP₃-induced Ca²⁺ release can be blocked by overexpressing IP₃ 5-phosphatase (5ppase), an IP₃ hydrolyzing enzyme (33, 53, 61, 63, 73). This 5ppase-dependent blockade of IP₃ signaling in PCs of SCA2 transgenic mice alleviates the SCA2 phenotype (55). These results support the notion that enhanced IP₃-induced Ca²⁺ signaling underlies SCA2 pathogenesis.

Another form of neurodegenerative disease, SCA3, is caused by CAG repeat expansion in the ataxin-3 gene, which results in neuronal degeneration in the substantia nigra and pontine nuclei (38). Here, the mutant form of ataxin-3 specifically binds and enhances IP₃R1, similar to mutant Htt and ataxin-2 proteins (19) (Fig. 2). Furthermore, RyR inhibition by dantrolene prevents neuronal loss and alleviates motor coordination deficits in mutant ataxin-3-expressing mice (19). Therefore, overactivation of IP₃R1- and RyR-mediated Ca²⁺ release from the ER may be involved in SCA3 pathogenesis. Furthermore, genetic studies of human SCA15 have revealed total or partial deletion as well as a missense mutation of the IP₃R1 gene (39, 57, 64).

Neuronal Cell Death Induced by NO-Induced Activation of RyR

Excessive neuronal activation by the excitatory neurotransmitter, glutamate, often leads to neuronal cell death. This pathological process is referred to as excitotoxicity and is encountered in various disease states, including brain ischemia and epileptic seizures. Brain NO concentration is increased owing to activation of NO synthase (NOS) both during ischemia and after reperfusion (70). NO generated by neuronal-type NOS (nNOS or NOS1) is implicated in excitotoxic neuronal death, because excitotoxic neuronal death is ameliorated in NOS1-knockout (KO) mice in disease models such as the middle cerebral artery occlusion (MCAO) model of stroke (45, 51) (Fig. 3) and kainic acid (KA) model of temporal lobe epilepsy (89).

How does an increase in NO concentration lead to neuronal death? When NO is simultaneously generated along with superoxide, peroxynitrite is also generated, which is a highly cytotoxic oxidant implicated in neuronal death (12, 36, 87, 117). On the contrary, it has been shown that NO may modulate the function of various proteins through S-nitrosylating cysteine residues on target proteins (42, 49, 83) (Fig. 4A). Recent studies indicate that S-nitrosylation-mediated modulation of RyR1 function is involved in excitotoxic neuronal death (51, 78).

FIG. 4.

NICR induced by S -nitrosylation of Cys-3636 in mouse RyR1. (A) S-nitrosylation reaction of a cysteine residue within a protein. (B) Schema showing the position of Cys-3636 in the mouse RyR1 channel. (C) NO-induced intracellular Ca²⁺ increase in neurons. Application of the NO donor, 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC7), induced increased [Ca²⁺]_i in neurons from wild-type (Ryr1 ^WT) mice, while no significant [Ca²⁺]_i increase was observed in Ryr1 ^C3636A neurons. Modified from Mikami et al. (78). [Ca²⁺]_i, intracellular Ca²⁺ concentration; NICR, nitric oxide-induced Ca²⁺ release.

The effect of NO on RyR1 function was first studied in skeletal muscle cells, in which abundantly expressed RyR1 is involved in excitation/contraction coupling. Accordingly, S-nitrosylation of one of the cysteine residues (Cys-3635 in rabbit/human RyR1) was shown to enhance channel opening (94, 111, 112). On increased NO concentration, increased [Ca²⁺]_i owing to Ca²⁺ release via RyR1 has been observed in central neurons, and is hereafter referred to as NO-induced Ca²⁺ release (NICR) (51). The effect of NO has been studied in other RyR subtypes, with NO found to activate both RyR1 and RyR3, but not RyR2 (51).

Because RyR1 expression overlaps with NOS1 in various brain regions, and because NOS1 is a key molecule in excitotoxicity, involvement of NICR in excitotoxicity has been investigated. Indeed, there was a hint that RyR1 is associated with excitotoxicity, because dantrolene (an NICR inhibitor) ameliorates both brain infarction after MCAO (66) and seizure-induced neurodegeneration (5, 85, 93). When the effect of dantrolene was compared between wild-type and NOS1-KO mice, the ameliorating effect of dantrolene was absent in NOS1-KO mice (51) (Fig. 3). These results are consistent with the notion that NICR is involved in excitotoxicity.

To further clarify the role of NICR in excitotoxicity, NICR was genetically silenced in mice in which Cys-3636 (corresponding to Cys-3635 in rabbit/human) of RyR1 was replaced with alanine (Ryr1 ^C3636A mice) (78) (Fig. 4B). Appropriately, NICR was lost in cultured neurons prepared from Ryr1 ^C3636A mice (Fig. 4C). These NICR-deficient mice bleed and grow normally. When they are subjected to KA-induced epilepsy, their seizure score is the same as wild-type mice, indicating that their susceptibility to seizures is unchanged (Fig. 5A). Neuronal damage was observed in the CA3 region of the hippocampus in wild-type mice after KA-induced epilepsy (Fig. 5B) but was significantly ameliorated in Ryr1 ^C3636A mice (Fig. 5B). Furthermore, application of dantrolene also ameliorated KA-induced neuronal damage (Fig. 5B). These results indicate that NICR via RyR1 is involved in excitotoxicity and that NICR inhibitors may have therapeutic value in prevention of excitotoxicity. It remains to be clarified how NICR in neurons leads to neuronal death. Prolonged depletion of ER Ca²⁺ due to NICR may play a role.

FIG. 5.

NICR-induced neurodegeneration on epileptic seizure. (A) Severe temporal lobe epilepsy was induced by KA administration in both wild-type (Ryr1 ^WT) and Ryr1 ^C3636A mice. Limbic seizures were scored and plotted against time after KA administration. Subsequent administration of dantrolene (Dan) had no effect on seizure induction. (B) Neurodegeneration after KA-induced epilepsy was evaluated by staining with FJC, a marker of degenerating neurons. Dotted lines show the position of the hippocampal stratum pyramidale. Yellow (CA3) and white (CA1) boxed areas in upper panels are shown enlarged in bottom panels. Scale bar, 200 μm. (C) KA-induced neurodegeneration was selectively observed in the CA3 region and ameliorated by dantrolene administration in Ryr1 ^WT mice. Ryr1 ^C3636A mice showed no significant neurodegeneration. Error bars indicate s.e.m (n =28–40). Data are analyzed for significance using ANOVA followed by a Turkey-Kramer post-hoc test. **p <0.01. Modified from Mikami et al. (78). FJC, Fluoro-Jade C; KA, kainic acid.

Probing Ca²⁺ Dynamics Within the ER

As reviewed above, ER Ca²⁺ loading state, which determines the driving force for Ca²⁺ mobilization and regulates function of ER-resident proteins, is crucially involved in neuronal cell death. Therefore, direct monitoring of neuronal ER Ca²⁺ dynamics using genetically encoded ER Ca²⁺ indicators (13, 48, 79, 88, 98, 118, 125) may be instrumental in advancing our understanding of associated pathologies. In a pioneering work, one of those indicators was used to study ER Ca²⁺ dynamics in cultured fibroblasts expressing FAD-linked PS mutants (74), although further improvements of spatiotemporal resolution of ER Ca²⁺ imaging are needed for studies on in situ or in vivo neurons.

Recently developed ER Ca²⁺ indicators, for example, CEPIAs (calcium-measuring organelle-entrapped protein indicators) provide high-resolution visualization of ER Ca²⁺ dynamics in various types of cells, including neurons (115) (Fig. 6A). G-CEPIA1er (86) was used to visualize synaptically evoked ER Ca²⁺ dynamics in cerebellar PCs, which possess a well-developed ER network with a high density of IP₃R (72, 102) (Fig. 6B). In response to parallel fiber (PF)-dependent IP₃ production, transient and focal decreases in [Ca²⁺]_ER in dendrites and spines were observed in PCs (Fig. 6B). Refilling of ER Ca²⁺ after PF-induced local depletion mainly occurred through lateral Ca²⁺ diffusion within the ER network, together with a minor contribution of SERCA-dependent Ca²⁺ reuptake (Fig. 6B). Repetitive climbing fiber (CF) stimulation, which induces dendrite-wide Ca²⁺ spikes via VGCC (56), results in an accumulating increase in [Ca²⁺]_ER throughout the dendrite (Fig. 6C). CF-induced responses reach a plateau after 10–20 stimulation pulses, likely because [Ca²⁺]_ER reaches a new equilibrium during repetitive Ca²⁺ spikes (Fig. 6C). Elevated [Ca²⁺]_ER returned to basal levels within a few minutes after cessation of CF inputs (Fig. 6C), which is consistent with previous observations showing that the potentiating effect of preceding depolarization lasts a few minutes (14, 35, 44, 108). Thus, G-CEPIA1er enables visualization of synaptically evoked ER Ca²⁺ dynamics at the individual spine level.

FIG. 6.

Visualization of neuronal ER Ca²⁺ dynamics using a CEPIA. (A) Schema of newly developed Ca²⁺ indicator CEPIA for visualization of ER luminal Ca²⁺ dynamics. Ca²⁺ affinity was optimized to match the ER concentration range by mutating amino acids in the Ca²⁺ binding domains of genetically encoded cytosolic Ca²⁺ indicator (cytosolic GECI). (B) Decrease and subsequent recovery in [Ca²⁺]_ER were visualized using G-CEPIA1er. PC dendritic segments and corresponding fluorescence traces on PF input (gray vertical lines) are color coded (magenta, orange, and green). The responses became smaller in magnitude and slower in onset according to segment distance from the input site. This wave-like propagation of the G-CEPIA1er response indicates lateral diffusion of luminal Ca²⁺ after PF-induced local depletion. Scale bar, 5 μm. (C) Activity-dependent ER Ca²⁺ filling. Time course of G-CEPIA1er fluorescence in a stimulated PC (magenta) and nonstimulated neighboring PC (green) on repetitive CF input (gray vertical lines). CF-induced ER Ca²⁺ overfilling and subsequent slow Ca²⁺ leakage in dendrites. Scale bar, 20 μm. Modified from Okubo et al. (86). [Ca²⁺]_ER, intraluminal free Ca²⁺ concentration within the ER; CEPIA, calcium-measuring organelle-entrapped protein indicator; CF, climbing fiber; PC, Purkinje cell; PF, parallel fiber.

Other high-performance ER Ca²⁺ indicators have been developed by different groups (50, 84). As in the case of G-CEPIA1er, the low-affinity version of GCaMP6 enables visualization of ER Ca²⁺ dynamics in the small compartment such as presynaptic boutons (50). A ratiometric Ca²⁺ sensor of the green fluorescent protein-aequorin protein has an advantage in the quantification of [Ca²⁺]_ER as in the case of other ratiometric indicators such as GEM-CEPIA1er (84). Analysis of ER Ca²⁺ dynamics under pathological conditions with high spatiotemporal resolution using these newly developed ER Ca²⁺ indicators may shed new light on the study of neurodegenerative diseases.

Perspectives

In this review, we have summarized current knowledge on involvement of ER Ca²⁺ signaling in neuronal cell death and neurodegeneration. Accumulating evidence allows us to recognize ER Ca²⁺ signaling as a promising therapeutic target for neuroprotection during various pathological conditions. The use of genetic methods to inhibit IP₃ signaling or new ER Ca²⁺ indicators may help advance our understanding of the role of ER Ca²⁺ dynamics in neurodegenerative disease. Such future studies on ER Ca²⁺ signaling are expected to provide progress for unmet medical needs in neurodegenerative disease.

Footnotes

Acknowledgments

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Nos. JP16K08543 [Y.O.], JP13J00025, and JP15K08227 [Y.M.], JP15H05648 [K.K.], and JP21229004 and JP25221304 [M.I.]), as well as grants from the Tokyo Society of Medical Sciences (Y.O.) and Pharmacological Research Foundation (Y.O.), and project research grants from Toho University (Y.M.).

Abbreviations Used

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Role of Endoplasmic Reticulum-Mediated Ca 2+ Signaling in Neuronal Cell Death

Abstract

Significance:

Recent Advances:

Critical Issues:

Future Directions:

Introduction

Neuronal ER Ca2+ Signaling

Disrupted Ca2+ Loading in the ER and Neuronal Cell Death

Disrupted Ca2+ Release and Neurodegeneration

Neuronal Cell Death Induced by NO-Induced Activation of RyR

Probing Ca2+ Dynamics Within the ER

Perspectives

Footnotes

Acknowledgments

Abbreviations Used

References

Neuronal ER Ca²⁺ Signaling

Disrupted Ca²⁺ Loading in the ER and Neuronal Cell Death

Disrupted Ca²⁺ Release and Neurodegeneration

Probing Ca²⁺ Dynamics Within the ER