The gain-of-function enhancement of IP3-receptor channel gating by familial Alzheimer's disease-linked presenilin mutants increases the open probability of mitochondrial permeability transition pore

Toglia, Patrick; Ullah, Ghanim

doi:10.1016/j.ceca.2016.05.002

Cited by 27 publications

(30 citation statements)

References 62 publications

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“…Using experimental data on IICR, together with a computational model of cell bioenergetics, a data-driven Markov chain model for IP 3 R gating, and a model for the dynamics of the mitochondrial permeability transition pore (mPTP) the difference in mPTP opening in WT and mutant PS cells was shown. No mPTP opening occurred in control WT cells whereas mPTP opened in cells with mutant PS [113]. It was reasoned that mutant PS causes disturbed IICR that activates the mitochondrial calcium uniporter leading to the mPTP opening and eventually to cell death [113,114].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

“…No mPTP opening occurred in control WT cells whereas mPTP opened in cells with mutant PS [113]. It was reasoned that mutant PS causes disturbed IICR that activates the mitochondrial calcium uniporter leading to the mPTP opening and eventually to cell death [113,114].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

“…The three mammalian IP 3 R isoforms contain 2700-2800 amino acid residues and share 60-70% sequence [105][106][107][108][109][110][111][112][113][114][115] identity and a common domain structure [22]. Recently the near-atomic (4.7 A) resolution cryo-electron microscopy (cryo-EM) structure of unbound IP 3 R1 purified from rat cerebellum was reported by Serysheva's group [23].…”

Section: Structure Function and Regulation Of Ip 3 Rsmentioning

confidence: 99%

“…The computational modeling of single IP 3 R activity was used to analyze and quantify the pathological enhancement of IP 3 R function by FADcausing mutant PS [112]. A combination of experimental data and computational modeling was used in further research for studying the differences in mitochondrial calcium influx in cells expressing WT and FAD-causing mutant PS [113]. Using experimental data on IICR, together with a computational model of cell bioenergetics, a data-driven Markov chain model for IP 3 R gating, and a model for the dynamics of the mitochondrial permeability transition pore (mPTP) the difference in mPTP opening in WT and mutant PS cells was shown.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

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

Egorova

Bezprozvanny

2018

The FEBS Journal

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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 ...

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Section: Alzheimer's Diseasementioning

confidence: 99%

Section: Alzheimer's Diseasementioning

confidence: 99%

Section: Structure Function and Regulation Of Ip 3 Rsmentioning

confidence: 99%

Section: Alzheimer's Diseasementioning

confidence: 99%

See 2 more Smart Citations

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

Egorova

Bezprozvanny

2018

The FEBS Journal

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“…[3, 4, 13]. Elucidating Ca 2+ signaling mechanism is therefore crucial for not only normal cell function but also understanding a wide range of pathological conditions such as neurological diseases [2, 5, 10, 11, 30], heart diseases [32], and mitochondrial dysfunction [15, 20, 30, 33, 34]. …”

Section: Introductionmentioning

confidence: 99%

Analyzing optical imaging of Ca 2+ signals via TIRF microscopy: The limits on resolution due to chemical rates and depth of the channels

2017

Self Cite

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High resolution total internal reflection (TIRF) microscopy (TIRFM) together with detailed computational modeling provides a powerful approach towards the understanding of a wide range of Ca2+ signals mediated by the ubiquitous inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) channel. Exploiting this fruitful collaboration further requires close agreement between the models and observations. However, elementary Ca2+ release events, puffs, imaged through TIRFM do not show the rapid single-channel openings and closings during and between puffs as are present in simulated puffs using data-driven single channel models. TIRFM also shows a rapid equilibration of 10ms after a channel opens or closes which is not achievable in simulation using standard Ca2+ diffusion coefficients and reaction rates between indicator dye and Ca2+. Furthermore, TIRFM imaging cannot decipher the depth of the channel with respect to the microscope, which will affect the change in fluorescence that the microscope detects, thereby affecting its sensitivity to fast single-channel activity. Using the widely used Ca2+ diffusion coefficients and reaction rates, our simulations show equilibration rates that are eight times slower than TIRFM imaging. We show that to get equilibrium rates consistent with observed values, the diffusion coefficients and reaction rates have to be significantly higher than the values reported in the literature, and predict the channel depth to be 200–250nm. Finally, we show that with the addition of noise, short events due to 1–2ms opening and closing of channels that are observed in computational models can be missed in TIRFM.

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Cardiovascular‐specific PSEN1 deletion leads to abnormalities in calcium homeostasis

Song

Zhao

Yang

et al. 2022

Cell Biology International

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Mutations of PSEN1 have been reported in dilated cardiomyopathy pedigrees. Understanding the effects and mechanisms of PSEN1 in cardiomyocytes might have important implications for treatment of heart diseases. Here, we showed that PSEN1 was downregulated in ischemia‐induced failing hearts. Functionally, cardiovascular specific PSEN1 deletion led to spontaneous death of the mice due to cardiomyopathy. At the age of 11 months, the ratio of the heart weight/body weight was slightly lower in the Sm22a‐PSEN1‐KO mice compared with that of the WT mice. Echocardiography showed that the percentage of ejection fraction and fractional shortening was significantly reduced in the Sm22a‐PSEN1‐KO group compared with the percent of these measures in the WT group, indicating that PSEN1‐KO resulted in heart failure. The abnormally regulated genes resulted from PSEN1‐KO were detected to be enriched in muscle development and dilated cardiomyopathy. Among them, several genes encode Ca2+ ion channels, promoting us to investigate the effects of PSEN1 KO on regulation of Ca2+ in isolated adult cardiomyocytes. Consistently, in isolated adult cardiomyocytes, PSEN1‐KO increased the concentration of cytosolic Ca2+ and reduced Ca2+ concentration inside the sarcoplasmic reticulum (SR) lumen at the resting stage. Additionally, SR Ca2+ was decreased in the failing hearts of WT mice, but with the lowest levels observed in the failing hearts of PSEN1 knockout mice. These results indicate that the process of Ca2+ release from SR into cytoplasm was affected by PSEN1 KO. Therefore, the abnormalities in Ca2+ homeostasis resulted from downregulation of PSEN1 in failing hearts might contribute to aging‐related cardiomyopathy, which might had important implications for the treatment of aging‐related heart diseases.

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The gain-of-function enhancement of IP3-receptor channel gating by familial Alzheimer's disease-linked presenilin mutants increases the open probability of mitochondrial permeability transition pore

Cited by 27 publications

References 62 publications

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

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

Analyzing optical imaging of Ca 2+ signals via TIRF microscopy: The limits on resolution due to chemical rates and depth of the channels

Cardiovascular‐specific PSEN1 deletion leads to abnormalities in calcium homeostasis

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