ReviewRoles of inositol 1,4,5-trisphosphate receptors in spinocerebellar ataxias
Introduction
Modulation of the cytoplasmic free calcium (Ca2+) concentration is a universal intracellular signaling system involved in the regulation of diverse biological processes, including learning and memory, axonal transport, cell excitability, synaptic transmission, cell division, cell development, and apoptosis (Foskett et al., 2007, Bezprozvanny, 2010, Finch et al., 2012; Stutzmann and Mattson, 2011, Goto and Mikoshiba, 2011). Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are a group of Ca2+ channels localized in the endoplasmic reticulum (ER) membrane (Foskett et al., 2007, Bezprozvanny, 2005). They function to release Ca2+ from the ER, the major intracellular Ca2+ storage organelle, into the cytoplasm in response to the binding of IP3, an intracellular second messenger, which is generated through hydrolysis of phosphatidyl-inositol 4,5-bisphosphate by phospholipases Cβ and Cγ (Fig. 1A). This hydrolysis is triggered by binding of the ligand to G protein-coupled or tyrosine phosphorylation-coupled receptors. IP3Rs, as well as other intracellular membrane Ca2+ channels including the ryanodine receptor (RyR), play a key role in the regulation of intracellular Ca2+ concentration (Fig. 1A).
Several lines of evidence suggest that aberrant IP3R-mediated Ca2+ signaling is implicated in the pathogenesis of spinocerebellar ataxias (SCAs), as well as other age-related neurodegenerative diseases, including Alzheimer's disease and Huntington's disease (Berridge, 2010, Bezprozvanny, 2011). In this review, we focus on the molecular basis of spinocerebellar ataxia types 15 (SCA15) and 29 (SCA29), which are caused by deletions or misssense mutations in the IP3R type 1 gene. In addition, we discuss other SCAs whose pathogenesis may be linked to aberrant activation of IP3R-mediated Ca2+ signaling.
Section snippets
Isoforms and structures of IP3Rs
IP3Rs are ubiquitously expressed in all cell types in the mammalian body. Three IP3R isoforms, types 1 (IP3R1), 2 (IP3R2), and 3 (IP3R3), are expressed in mammals including humans (Furuichi et al., 1994, Mikoshiba et al., 1993, Foskett et al., 2007, Taylor et al., 1999, Taylor et al., 2004, Stutzmann and Mattson, 2011, Goto and Mikoshiba, 2011) and share 60–70% homology in terms of amino acid sequence (Furuichi et al., 1994, Michikawa et al., 1996). Most tissues express more than one of these
ITPR1-knockout mice
Homozygous ITPR1-knockout mice, in which cytosolic IP3-induced Ca2+ release is almost completely deficient, generally die in utero, indicating that IP3R1 is essential for embryonic development. Even if they survive, the mice exhibit severe ataxia and tonic or tonic-clonic seizures and die by weaning age or before (Matsumoto et al., 1996, Matsumoto and Nagata, 1999). Neurophysiological analysis has shown that long-term depression (LTD) is completely diminished in cerebellar Purkinje cells (Inoue
ITPR1 deletion in humans
In 2007, heterozygous large deletions encompassing exons 1–10, 1–40, and 1–44 of ITPR1 and the adjoining sulfatase modifying factor 1 (SUMF1) were identified in unrelated Australian and British families with SCA15 (van de Leemput et al., 2007), which is a neurodegenerative disorder clinically characterized by autosomal dominant inheritance, pure cerebellar ataxia, and very slow progression (Storey et al., 2001, Gardner et al., 2005, Knight et al., 2003, Hara et al., 2004). Brain magnetic
Aberrant IP3R-mediated Ca2+ signaling in ataxias caused by expanded polyglutamine (polyQ) stretches
SCA types 2 (SCA2) and 3 (SCA3) are neurodegenerative ataxias showing autosomal dominant inheritance caused by expansions of CAG repeats that encode abnormally expanded polyglutamine (polyQ) in the ataxin-2 (ATXN2) and ataxin-3 (ATXN3) proteins, respectively (Zoghbi and Orr, 2000, Williams and Paulson, 2008, La Spada and Taylor, 2010, Costa Mdo and Paulson, 2012). The mutant ATXN2 and ATXN3 proteins with abnormal polyQ expansion show a tendency to aggregate in cells, resulting in the formation
Roles of IP3R2 and IP3R3 in neurological disorders
In current knowledge, ITPR2 and ITPR3 have not been causal genes for neurological disorders yet. Recently, a homozygous missense mutation in ITPR2 was identified in a family exhibiting anhidrosis (Klar et al., 2014). As well as humans, homozygous ITPR2-deficient mice exhibit decreased sweat secretion, but not neurological symptoms.
Concluding remarks
We have discussed the molecular basis of SCAs, including SCA15, SCA29, CARP-related ataxia, SCA2, and SCA3, whose pathogenesis is related to aberrant IP3R-mediated Ca2+ signaling. There is increasing evidence that aberrant IP3R1-mediated Ca2+ signaling is also implicated in other age-related neurological diseases including Alzheimer's and Huntington diseases, as well as SCAs. Despite many advances in our understanding of these fatal neurological disorders, no preventive treatment yet exists.
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 (#25461272), and a Grant-in-Aid for the Research Committee for Ataxic Diseases from the Ministry of Health, Labor and Welfare, Japan.
References (90)
- et al.
IRBIT suppresses IP3 receptor activity by competing with IP3 for the common binding site on the IP3 receptor
Mol. Cell
(2006) The inositol 1,4,5-trisphosphate receptors
Cell Calcium
(2005)- et al.
Intracellular channels
Curr. Opin. Neurobiol.
(1994) - et al.
Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3
J. Biol. Chem.
(2007) - et al.
Determinants of postsynaptic Ca2+ signaling in Purkinje neurons
Cell Calcium
(2005) - et al.
Neuronal plasticity in hippocampal mossy fiber-CA3 synapses of mice lacking the inositol-1,4,5-trisphosphate type 1 receptor
Brain Res.
(2001) - et al.
Spinocerebellar ataxia type 15 (sca15) maps to 3p24.2-3pter: exclusion of the IP3R1 gene, the human orthologue of an ataxic mouse mutant
Neurobiol. Dis.
(2003) - et al.
Structural basis of binding of P-body-associated proteins GW182 and ataxin-2 by the Mlle domain of poly(A)-binding protein
J. Biol. Chem.
(2010) - et al.
Molecular cloning of a cDNA for the human inositol 1,4,5-trisphosphate receptor type 1, and the identification of a third alternatively spliced variant
Brain Res. Mol. Brain Res.
(1995) - et al.
Motor discoordination in mutant mice heterozygous for the type 1 inositol 1,4,5-trisphosphate receptor
Behav. Brain Res.
(2001)
Machado-Joseph disease/spinocerebellar ataxia type 3
Handb. Clin. Neurol.
Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3
Neuron
An integrative approach to gain insights into the cellular function of human ataxin-2
J. Mol. Biol.
IP(3) receptors: the search for structure
Trends Biochem. Sci.
Expression of inositol trisphosphate receptors
Cell Calcium
Functional characterization of the type 1 inositol 1,4,5-trisphosphate receptor coupling domain SII(+/-) splice variants and the Opisthotonos mutant form
Biophys. J.
Ataxin-2 associates with rough endoplasmic reticulum
Exp. Neurol.
Polyglutamine neurodegeneration: protein misfolding revisited
Trends Neurosci.
Functional characterization of the P1059L mutation in the inositol 1,4,5-trisphosphate receptor type 1 identified in a Japanese SCA15 family
Biochem. Biophys. Res. Commun.
Structural and functional analysis of ataxin-2 and ataxin-3
Eur. J. Biochem.
Carbonic anhydrase-related protein VIII: autoantigen in paraneoplastic cerebellar degeneration
Ann. Neurol.
Calcium hypothesis of Alzheimer's disease
Pflugers Arch.
Role of inositol 1,4,5-trisphosphate receptors in pathogenesis of Huntington's disease and spinocerebellar ataxias
Neurochem. Res.
Calcium signaling and neurodegeneration
Acta Naturae
A novel spinocerebellar ataxia type 15 family with involuntary movements and cognitive decline
Eur. J. Neurol.
Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3
J. Neurosci.
Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins
J. Neurosci.
ATX-2, the C. elegans ortholog of ataxin 2, functions in translational regulation in the germline
Development
Toward understanding Machado-Joseph disease
Prog. Neurobiol.
Two Italian families with IP3R1 gene deletion presenting a broader phenotype of SCA15
Cerebellum
Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus
Neurology
Calcium as a trigger for cerebellar long-term synaptic depression
Cerebellum
Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia
JAMA Neurol.
Inositol trisphosphate receptor Ca2+ release channels in neurological diseases
Pflugers Arch.
Inositol trisphosphate receptor Ca2+ release channels
Physiol. Rev.
Synaptic plasticity in hippocampal CA1 neurons of mice lacking type 1 inositol-1,4,5-trisphosphate receptors
Learn Mem.
Development of a multiplex ligation-dependent probe amplification assay for diagnosis and estimation of the frequency of spinocerebellar ataxia type 15
Clin. Chem.
Spinocerebellar ataxia type 15
Cerebellum
Inositol 1,4,5-trisphosphate receptor-mediated calcium release in Purkinje cells: from molecular mechanism to behavior
Cerebellum
Molecular mechanisms for regulation of AMPAR trafficking by PICK1
Biochem. Soc. Trans.
Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus
Neurology
Total deletion and a missense mutation of IP3R1 in Japanese SCA15 families
Neurology
Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5-trisphosphate receptor type 1
Biochem. J.
Inositol 1,4,5-trisphosphate receptor type 1 in granule cells, not in Purkinje cells, regulates the dendritic morphology of Purkinje cells through brain-derived neurotrophic factor production
J. Neurosci.
Missense mutations in IP3R1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia
Orphanet J. Rare Dis.
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