IP₃ receptor mutations and brain diseases in human and rodents

Abstract

The inositol 1,4,5-trisphosphate receptor (IP 3 R) is a huge Ca 2+ channel that is localized at the endoplasmic reticulum.

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

“…Deregulation of calcium signaling in neurons may also play a role in the pathogenesis of SCA types 15/16 and 29 (SCA15/16 and SCA29), Gillespie's syndrome, sensory ataxia and some other neurodegenerative disorders (Table 1). These data indicated that IICR might be one of the causes of pathophysiological events in neuronal cells [7,8].…”

“…The three genes that encode the three IP 3 R subtypes, IP 3 R1, IP 3 R2 and IP 3 R3, have been identified and cloned in mammalian cells [15]. The expression of different IP 3 R subtypes is cell type-dependent [8,16]; for example, cerebellar PCs mainly express IP 3 R1, insulin-secreting b-cells express IP 3 R3 [17] and cardiac myocytes express predominantly IP 3 R2 [18]. The IP 3 R1 isoform is observed predominantly in central nervous system neurons, but most other tissues express at least two and often all three IP 3 R isoforms at different ratios.…”

Structure and Function of IP3Receptors

“…The subunits are enormous (∼2700 residues), such that IP 3 Rs and RyRs (which are even larger, 4 × ∼5000 residues/RyR) are the largest known ion channels. The IP 3 R subtypes differ in their patterns of expression between tissues ) and perhaps in their subcellular distributions (Vervloessem et al 2015), they have different affinities for IP 3 (IP 3 R2 > IP 3 R1 > IP 3 R3) (Iwai et al 2007), they differ in their associations with other proteins and in their modulation by additional signals (Prole and Taylor 2016), they appear to differ in their capacity to sustain oscillatory Ca 2+ signals (Miyakawa et al 1999;Wang and Yule 2018), and the functional consequences of perturbing IP 3 Rs differ for the different subtypes (Hisatsune and Mikoshiba 2017). Despite the differences, the core functional properties of all IP 3 Rs are similar and so too are their structures, consistent with the sequence conservation (∼70%) between subtypes (Fan et al 2015(Fan et al , 2018Paknejad and Hite 2018).…”

“…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.…”