Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

Terry, Lara E.; Alzayady, Kamil J.; Furati, Esraa; Yule, David I.

doi:10.1166/msr.2018.1075

Cited by 28 publications

(34 citation statements)

References 72 publications

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“…IP3R1 is highly expressed in the nervous system (35) and mutations result in broad range of disease phenotypes: ataxia alone or ataxia with cognitive difficulties, iris hypoplasia and/or cerebellar hypotrophy. Indeed, there is a growing list of missense (47)(48)(49)(50)(51)(52)(53)(54)(55), nonsense, insertion/deletion, and splice mutations (58,59) scattered throughout the IP3R1 gene ( Figure 1). Nevertheless, how IP3R1 mutations affect channel activity and how these mutations lead to pathogenesis remains to be elucidated.…”

Section: Resultsmentioning

confidence: 99%

Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function

Terry

Alzayady

Wahl

et al. 2020

Journal of Biological Chemistry

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The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IP3Rs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome and generalized anhidrosis. However, how these mutations affect IP3R function, and how the perturbation of associated calcium signals contribute to the pathogenesis and severity of these diseases, remains largely uncharacterized. Moreover, many of these diseases occur as the result of autosomal dominant inheritance, suggesting that wild type and mutant subunits associate in heterotetrameric channels. How the incorporation of different numbers of mutant subunits within the tetrameric channels affects its activities and results in different disease phenotypes is also unclear. In this report, we investigated representative disease-associated missense mutations to determine their effects on IP3R channel activity. Additionally, we designed concatenated IP3R constructs to create tetrameric channels with a predefined subunit composition to explore the functionality of heteromeric channels. Using calcium imaging techniques to assess IP3R channel function, we observed that all the mutations studied resulted in severely attenuated Ca2+ release when expressed as homotetramers. However, some heterotetramers retained varied degrees of function dependent on the composition of the tetramer. Our findings suggest that the effect of mutations depends on the location of the mutation in the IP3R structure, as well as on the stoichiometry of mutant subunits assembled within the tetrameric channel. These studies provide insight into the pathogenesis and penetrance of these devastating human diseases.

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Section: Resultsmentioning

confidence: 99%

Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function

Terry

Alzayady

Wahl

et al. 2020

Journal of Biological Chemistry

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“…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).…”

Section: Ip 3 Receptors As Signaling Hubsmentioning

confidence: 99%

Structure and Function of IP₃Receptors

Prole

Taylor

2019

Cold Spring Harb Perspect Biol

137

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Inositol 1,4,5-trisphosphate receptors (IP 3 Rs), by releasing Ca 2+ from the endoplasmic reticulum (ER) of animal cells, allow Ca 2+ to be redistributed from the ER to the cytosol or other organelles, and they initiate store-operated Ca 2+ entry (SOCE). For all three IP 3 R subtypes, binding of IP 3 primes them to bind Ca 2+ , which then triggers channel opening. We are now close to understanding the structural basis of IP 3 R activation. Ca 2+ -induced Ca 2+ release regulated by IP 3 allows IP 3 Rs to regeneratively propagate Ca 2+ signals. The smallest of these regenerative events is a Ca 2+ puff, which arises from the nearly simultaneous opening of a small cluster of IP 3 Rs. Ca 2+ puffs are the basic building blocks for all IP 3 -evoked Ca 2+ signals, but only some IP 3 clusters, namely those parked alongside the ER-plasma membrane junctions where SOCE occurs, are licensed to respond. The location of these licensed IP 3 Rs may allow them to selectively regulate SOCE.

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“…Three IP 3 R isotypes, IP 3 R1, 2 and 3 are encoded by mammalian genomes ( Furuichi, 1994 ; Taylor et al, 1999 ). Of these, IP 3 R1 is the most prevalent isoform in neurons and is relevant in the context of several neurodegenerative disorders ( Terry et al, 2018 ). Human mutations in IP 3 R1 cause Spinocerebellar ataxia 15 (SCA15), SCA29 and Gillespie syndrome ( Hasan and Sharma, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Modulation of flight and feeding behaviours requires presynaptic IP3Rs in dopaminergic neurons

Sharma

Hasan

2020

eLife

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Innate behaviours, although robust and hard wired, rely on modulation of neuronal circuits, for eliciting an appropriate response according to internal states and external cues. Drosophila flight is one such innate behaviour that is modulated by intracellular calcium release through inositol 1,4,5-trisphosphate receptors (IP3Rs). Cellular mechanism(s) by which IP3Rs modulate neuronal function for specific behaviours remain speculative, in vertebrates and invertebrates. To address this, we generated an inducible dominant negative form of the IP3R (IP3RDN). Flies with neuronal expression of IP3RDN exhibit flight deficits. Expression of IP3RDN helped identify key flight-modulating dopaminergic neurons with axonal projections in the mushroom body. Flies with attenuated IP3Rs in these presynaptic dopaminergic neurons exhibit shortened flight bouts and a disinterest in seeking food, accompanied by reduced excitability and dopamine release upon cholinergic stimulation. Our findings suggest that the same neural circuit modulates the drive for food search and for undertaking longer flight bouts.

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Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

Cited by 28 publications

References 72 publications

Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function

Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function

Structure and Function of IP₃Receptors

Modulation of flight and feeding behaviours requires presynaptic IP3Rs in dopaminergic neurons

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Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

Cited by 28 publications

References 72 publications

Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function

Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function

Structure and Function of IP3Receptors

Modulation of flight and feeding behaviours requires presynaptic IP3Rs in dopaminergic neurons

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Structure and Function of IP₃Receptors