Review
Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders

https://doi.org/10.1016/S0166-2236(00)01548-4Get rights and content

Abstract

Endoplasmic reticulum (ER) is a multifaceted organelle that regulates protein synthesis and trafficking, cellular responses to stress, and intracellular Ca2+ levels. In neurons, it is distributed between the cellular compartments that regulate plasticity and survival, which include axons, dendrites, growth cones and synaptic terminals. Intriguing communication networks between ER, mitochondria and plasma membrane are being revealed that provide mechanisms for the precise regulation of temporal and spatial aspects of Ca2+ signaling. Alterations in Ca2+ homeostasis in ER contribute to neuronal apoptosis and excitotoxicity, and are being linked to the pathogenesis of several different neurodegenerative disorders, including Alzheimer’s disease and stroke.

Section snippets

ER Ca2+ signaling

Several proteins are housed in the ER that control movements of Ca2+ across its membrane under basal conditions and in response to environmental stimuli10. Under resting conditions the concentration of Ca2+ in the ER lumen is considerably higher (10–100 μm) than the Ca2+ concentration in the cytoplasm (100–300 nm). This Ca2+ gradient is maintained by an ATP-dependent pump called SERCA (smooth ER Ca2+ ATPase) in the ER membrane (Fig. 2a). ER also contains two types of Ca2+ channel, inositol

Developmental and synaptic plasticity

Roles for ER-mediated Ca2+ signaling in the regulation of neurite outgrowth and synaptogenesis are likely, but surprisingly underexplored. Studies of the expression of genes encoding IP3Rs and RyRs during development of the nervous system have established associations between different isoforms of these channels and processes such as neurite outgrowth and synaptogenesis. For example, IP31 is present in cortical neurons shortly after their migration from the ventricular zone, and its levels then

Apoptosis, excitotoxicity and neurodegenerative disorders

Apoptosis is a form of programmed cell death that normally occurs during the development of the nervous system, and can also occur in various pathological settings including Alzheimer’s, Parkinson’s and Huntington’s diseases, and stroke56, 57, 58. The biochemical cascades that lead to apoptotic cell death are being elucidated and involve activation of one or more members of a family of cysteine proteases called caspases, mitochondrial Ca2+ uptake and membrane-permeability transition, and

Conclusions and future directions

Mechanisms by which the ER controls neuronal Ca2+ homeostasis, and how this function of ER contributes to neuronal plasticity and death, are being elucidated. ER localization to dendrites, axons and their terminals (growth cones and synapses) provides for local control of Ca2+ signals that effect changes in the structure and function of neuronal circuits. Interactions of ER with Ca2+-regulating systems in the plasma membrane and mitochondria provide for complex spatial and temporal control of Ca

Acknowledgements

The authors’ research is supported by the National Institute on Aging and the Alzheimer’s Association (M.P.M.), the Medical Research Council of Canada (J.D.G. and P.N.S.), and the Alzheimer’s Society of Canada (J.D.G.).

References (85)

  • L.Y. Bourguignon et al.

    Identification of the ankyrin-binding domain of the mouse T-lymphoma cell inositol 1,4,5-trisphosphate (IP3) receptor and its role in the regulation of IP3-mediated internal Ca2+ release

    J. Biol. Chem.

    (1995)
  • M.D. Bootman

    Cooking with calciumthe recipes for composing global signals from elementary events

    Cell

    (1997)
  • Y. Ouyang

    Differential distribution and subcellular localization of ryanodine receptor isoforms in the chicken cerebellum during development

    Brain Res.

    (1997)
  • M.P. Mattson

    Neurotransmitters in the regulation of neuronal cytoarchitecture

    Brain Res. Rev.

    (1988)
  • S.B. Kater

    Calcium regulation of the neuronal growth cone

    Trends Neurosci.

    (1988)
  • M.P. Mattson

    Growth factor-mediated protection from excitotoxicity and disturbances in calcium and free radical metabolism

    Semin. Neurosci.

    (1993)
  • K.L. Lankford

    Blocking Ca2+ mobilization with thapsigargin reduces neurite initiation in cultured adult rat DRG neurons

    Dev. Brain Res.

    (1995)
  • P. Fossier

    Involvement of Ca2+ uptake by a reticulum-like store in the control of transmitter release

    Neuroscience

    (1992)
  • T. Linden

    Role of calcium in the activation of erp72 and heme oxygenase-1 expression on depletion of endoplasmic reticulum calcium stores in rat neuronal cell culture

    Neurosci. Lett.

    (1998)
  • P. Nicotera

    Neuronal cell deatha demise with different shapes

    Trends Pharmacol. Sci.

    (1999)
  • T. Takadera et al.

    Apoptotic cell death and CPP32-like activation induced by thapsigargin and their prevention by nerve growth factor in PC12 cells

    Biochim. Biophys. Acta

    (1998)
  • I. Mody et al.

    NMDA receptor-dependent excitotoxicitythe role of intracellular Ca2+ release

    Trends Pharmacol. Sci.

    (1995)
  • M.P. Mattson

    Acetylcholine potentiates glutamate-induced neurodegeneration in cultured hippocampal neurons

    Brain Res.

    (1989)
  • A. Parent

    Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1

    Neurobiol. Dis.

    (1999)
  • M.A. Leissring

    Presenilin-2 mutations modulate amplitude and kinetics of inositol 1,4,5-trisphosphate-mediated calcium signals

    J. Biol. Chem.

    (1999)
  • Z. Yu

    The endoplasmic reticulum stress-responsive protein GRP78 protects neurons against excitotoxicity and apoptosissuppression of oxidative stress and stabilization of calcium homeostasis

    Exp. Neurol.

    (1999)
  • A.J. Cross

    Loss of endoplasmic reticulum-associated enzymes in affected brain regions in Huntington’s disease and Alzheimer-type dementia

    J. Neurol. Sci.

    (1985)
  • E. Korkotian

    Elevation of intracellular glucosylceramide levels results in an increase in endoplasmic reticulum density and in functional calcium stores in cultured neurons

    J. Biol. Chem.

    (1999)
  • T.P. Cheng et al.

    Polarized compartmentalization of organelles in growth cones from developing optic tectum

    J. Cell Biol.

    (1985)
  • J.S. Deitch et al.

    An electron microscopic analysis of hippocampal neurons developing in cultureearly stages in the emergence of polarity

    J. Neurosci.

    (1993)
  • T. Kanaseki

    Rough surfaced smooth endoplasmic reticulum in rat and mouse cerebellar Purkinje cells visualized by quick-freezing techniques

    Cell Struct. Funct.

    (1998)
  • L. Levesque

    Developmental expression of wild-type and mutant presenilin-1 in hippocampal neurons from transgenic miceevidence for novel species-specific properties of human presenilin-1

    Mol. Med.

    (1999)
  • M.E. Dailey et al.

    Dynamics of the endoplasmic reticulum and other membranous organelles in growth cones of cultured neurons

    J. Neurosci.

    (1989)
  • T. Banno et al.

    Conformational changes of the smooth endoplasmic reticulum are facilitated by l-glutamate and its receptors in rat Purkinje cells

    J. Comp. Neurol.

    (1998)
  • C.M. Waterman-Storer et al.

    Endoplasmic reticulum membrane tubules are distributed by microtubules in living cells using three distinct mechanisms

    Curr. Biol.

    (1998)
  • J.S. Tabb

    Transport of ER vesicles on actin filaments in neurons by myosin V

    J. Cell Sci.

    (1998)
  • R. Rizzuto

    Close contacts with the endoplasmic reticulum as determinants of mitochondrial calcium responses

    Science

    (1998)
  • A.H. Sharp

    Differential immunohistochemical localization of inositol 1,4,5-trisphosphate- and ryanodine-sensitive Ca2+ release channels in rat brain

    J. Neurosci.

    (1993)
  • R. Etcheberrigaray

    Endoplasmic reticulum as a source of calcium in neurotransmitter secretion

    Ann. New York Acad. Sci.

    (1991)
  • M. Yamada

    The calmodulin-binding domain in the mouse type 1 inositol 1,4,5-trisphosphate receptor

    Biochem. J.

    (1995)
  • V.M. Pickel

    Ultrastructural localization of sorcin, a 22 kDa calcium binding protein, in the rat caudate-putamen nucleusassociation with ryanodine receptors and intracellular calcium release

    J. Comp. Neurol.

    (1997)
  • M.P. Mattson

    Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer’s disease

    J. Neurochem.

    (1998)
  • Cited by (434)

    View all citing articles on Scopus
    View full text