Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

Abstract

The inositol 1,4,5-trisphosphate receptor (IP 3 R) is an intracellular ion channel that mediates the release of calcium ions from the endoplasmic reticulum. It plays a role in basic biological functions, such as cell division, differentiation, fertilization and cell death, and is involved in developmental processes including learning, memory and behavior. Deregulation of neuronal calcium signaling results in disturbance of cell homeostasis, synaptic loss and dysfunction, eventually leading to cell death. Three IP 3 R subtypes have been identified in mammalian cells and the predominant isoform in neurons is IP 3 R type 1. Dysfunction of IP 3 R type 1 may play a role in the pathogenesis of certain neurodegenerative diseases as enhanced activity of the IP 3 R was observed in models of Huntington's disease, spinocerebellar ataxias and Alzheimer's disease. These results suggest that IP 3 R-mediated signaling is a potential target for treatment of these disorders. In this review we discuss the structure, functions and regulation of the IP 3 R in healthy neurons and in conditions of neurodegeneration. IntroductionInositol 1,4,5-trisphosphate receptors (IP 3 Rs) are a family of intracellular ion channels that mediate calcium (Ca 2+ ) release from the endoplasmic reticulum (ER) following stimulation by the second messenger inositol 1,4,5-trisphosphate (IP 3 ). Generation of IP 3 molecules is caused by the activation of phospholipase C in response to the activation of G proteincoupled receptors such as serotonergic receptors, adrenergic receptors, calcitonin receptors, histamine receptors, metabotropic glutamate receptors (mGluRs), Abbreviations AAV, adeno-associated virus; AD, Alzheimer's disease; ALG-2, apoptosis-linked gene 2; ARM, armadillo; Ab, beta amyloid; BH, Bcl-2 homology; CaBP1, calcium-binding protein 1; CTD, C-terminal domain; EM, electron microscopy; ER, endoplasmic reticulum; FAD, familial Alzheimer's disease; GRP78, 78-kDa glucose regulated protein; HAP1, huntingtin-associated protein 1; HD, Huntington's disease; HelD, helical domain; Htt, huntingtin; IBC, IP 3 -binding core; IICR, inositol 1,4,5-trisphosphate-induced calcium release; ILD, 'intervening lateral' domain; IP 3 , inositol 1,4,5-trisphosphate; IP 3 R1, IP 3 R type 1; IP 3 R, inositol 1,4,5-trisphosphate receptor; IRBIT, IP 3 R binding protein released with IP 3 ; KO, knock-out; LBD, ligand-binding domain; LNK, helical linker domain; MCI, mild cognitive impairment; mGluR, metabotropic glutamate receptor; mPTP, mitochondrial permeability transition pore; MSN, medium spiny neuron; NMDA, N-methyl-D-aspartate; NTR, Nterminal region; Opt, opisthotonos; PC, Purkinje cell; polyQ, polyglutamine; PS, presenilin; RyR, ryanodine receptor; SAD, sporadic Alzheimer's disease; SCA, spinocerebellar ataxia; SD, IP 3 -binding suppressor domain; SUMF1, sulfatase modifying factor 1; TG2, transglutaminase type 2; TMD, transmembrane domain; WT, wild-type; YAC, yeast artificial chromosome; b-TF, b-trefoil. 3547The (Fig. 1). Upon extracellular stimulation -by various ...

Structure and Function of IP3Receptors

“…Modulatory proteins also provide links between IP 3 Rs and human diseases, additional to those arising from loss or mutation of IP 3 Rs (Berridge 2016;Casey et al 2017;Hisatsune and Mikoshiba 2017;Terry et al 2018). The mutant forms of Huntingtin associated with Huntington's disease, mutant ataxins associated with spinocerebellar ataxias, and mutant presenilins associated with inherited forms of Alzheimer's disease, for example, have each been reported to enhance IP 3 -evoked Ca 2+ signals (Chen et al 2008;Cheung et al 2008Cheung et al , 2010Liu et al 2009;Egorova and Bezprozvanny 2018).…”

“…We focus on recent progress toward understanding the structural basis of IP 3 R activation, evidence that IP 3 Rs are regulated by many additional proteins, and the organization of IP 3 Rs within ER membranes and the implications of that for SOCE. Other reviews provide readers with broader overviews (Foskett et al 2007), historical perspectives (Berridge 2005;Rossi and Taylor 2019), and more focused considerations of IP 3 Rs and disease (Berridge 2016;Hisatsune and Mikoshiba 2017;Egorova and Bezprozvanny 2018), their regulation by proteolysis (Wang and Yule 2018) and other signals (Prole and Taylor 2016;Taylor 2017), the evolution of IP 3 Rs (Alzayady et al 2015), and relationships between SOCE and IP 3 Rs (Taylor and Machaca 2019;Thillaiappan et al 2019). We begin with a short overview of IP 3 Rs.…”

The erlin2 T65I mutation inhibits erlin1/2 complex–mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3-phosphate binding

“…First, as T65I erlin2 is unable to interact with activated IP3Rs, IP3R ERAD is impaired. The expected chronic perturbation of IP3R levels and Ca 2+ handling could contribute to neurodegeneration (46). This logic parallels the effects of the R199C mutation to RNF170, which perturbs Ca 2+ signaling (11) and causes neurodegeneration and autosomal-dominant sensory ataxia (47).…”

Different faces of neurodegeneration

“…They note that enhanced activity of the IP 3 R was observed in models of Huntington's disease, spinocerebellar ataxias and Alzheimer's disease, which suggest IP 3 R-mediated signalling as a potential target for treatment of these disorders [6]. Polina Egorova and Ilya Bezprozvanny draw the attention of readers to components of the calcium signalling systeminositol 1,4,5-trisphosphate receptors (IP 3 R)and discuss their functions and regulation in healthy neurons and during neurodegeneration.…”

“…Polina Egorova and Ilya Bezprozvanny draw the attention of readers to components of the calcium signalling systeminositol 1,4,5-trisphosphate receptors (IP 3 R)and discuss their functions and regulation in healthy neurons and during neurodegeneration. They note that enhanced activity of the IP 3 R was observed in models of Huntington's disease, spinocerebellar ataxias and Alzheimer's disease, which suggest IP 3 R-mediated signalling as a potential target for treatment of these disorders [6].…”