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IP3 Receptors in Neurodegenerative Disorders: Spinocerebellar Ataxias and Huntington’s and Alzheimer’s Diseases

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Pathologies of Calcium Channels

Abstract

Modulation of intracellular calcium concentration is a ubiquitous signaling system involved in numerous biological processes in diverse cell types. Alterations of intracellular calcium homeostasis have been implicated in age-related neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and spinocerebellar ataxias (SCAs). Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), calcium release channels in the ER membrane, play a key role in regulating intracellular calcium concentration. IP3R type 1 (IP3R1), a major neuronal type of IR3R, is expressed ubiquitously and is involved in diverse biological processes. Cerebellar Purkinje cells are mainly affected by alterations in IP3R1. Heterozygous deletion or missense mutations in ITPR1, the IP3R1 gene, result in autosomal dominantly inherited ataxias, including SCA type 15 or 29. In addition, mutations in carbonic anhydrase-related protein VIII, which suppresses the binding ability of IP3 to IP3R1, cause recessively, inherited ataxia. These results indicate that IP3R1-mediated calcium signaling has an important role in maintaining the function of Purkinje cells. Moreover, cytosolic calcium overload with excessive IP3R1 activity has been implicated in pathogenesis of other neurodegenerative diseases, including SCA type 2, SCA type 3, Huntington’s disease, and Alzheimer’s disease, where dysregulation of IP3R1-mediated calcium signaling may link to the pathogenesis.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid β

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ATXN2:

Ataxin-2

ATXN3:

Ataxin-3

CAMRQ3:

Cerebellar ataxia and mental retardation with or without quadrupedal locomotion 3

CARP:

Carbonic anhydrase-related protein VIII

ER:

Endoplasmic reticulum

HAP1:

Htt-associated protein1

HD:

Huntington’s disease

Htt:

Huntingtin

mHtt:

Mutant huntingtin

IP3 :

Inositol 1,4,5-trisphosphate

IP3R:

IP3 receptor

IP3R1:

Inositol 1,4,5-trisphosphate receptor type 1

LTD:

Long-term depression

mGluR:

Metabotropic glutamate receptors

MSN:

Medium spiny neuron

nAChR:

Nicotinic acetylcholine receptor

NCX:

Sodium-calcium exchanger

NMDA:

N-methyl-d-aspartic acid

PMCA:

Plasma membrane calcium ATPase

PS:

Presenilin

RyR:

Ryanodine receptor

SCA:

Spinocerebellar ataxia

SERCA:

Sarco-/endoplasmic reticulum calcium ATPase

SUMF1:

Sulfatase modifying factor 1

VGCC:

Voltage-gated calcium channel

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Acknowledgments

This study was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and a Grant-in-Aid for the Research Committee for Ataxic Diseases from the Ministry of Health, Labor and Welfare, Japan.

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Authors and Affiliations

  1. Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan

    Masayoshi Tada & Masatoyo Nishizawa

  2. Department of Molecular Neuroscience, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan

    Osamu Onodera

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  1. Masayoshi Tada
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  2. Masatoyo Nishizawa
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  3. Osamu Onodera
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Correspondence to Osamu Onodera .

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Editors and Affiliations

  1. Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada

    Norbert Weiss

  2. Department of Neurophysiology and Pharmacology, Medical University Vienna, Vienna, Austria

    Alexandra Koschak

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Tada, M., Nishizawa, M., Onodera, O. (2014). IP3 Receptors in Neurodegenerative Disorders: Spinocerebellar Ataxias and Huntington’s and Alzheimer’s Diseases. In: Weiss, N., Koschak, A. (eds) Pathologies of Calcium Channels. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40282-1_28

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