Regulation of ryanodine receptor-mediated calcium signaling by presenilins

Payne, Andrew J.; Kaja, Simon; Koulen, Peter

doi:10.14800/rci.449

Cited by 6 publications

(1 citation statement)

References 21 publications

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“…S2 ), such as the RyR inhibitor homer1b ( Feng et al, 2008 ), and genes whose expression is regulated by RyR activity, such as Wingless-type 2 paralogs, wnt2ba and wnt2bb ( Wayman et al, 2012b ). We also determined transcription of ER transmembrane proteins presenilin 1 and 2 ( psen1, psen2 ), which influence the probability and frequency of RyR opening, and triadin ( trdn ), which forms a complex with RyRs to modulate channel opening depending on luminal Ca 2+ status ( Györke et al, 2004 ; Payne, Kaja & Koulen, 2015 ). Finally, we investigated transcription of two types of voltage dependent L-type calcium channels ( cacna1c, cacna1sa ), which regulate entry of extracellular calcium, thereby activating RyR to trigger calcium release from internal stores ( Lipscombe, Allen & Toro, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic profiling of mTOR and ryanodine receptor signaling molecules in developing zebrafish in the absence and presence of PCB 95

Frank

Miller

Connon

et al. 2017

PeerJ

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The mechanistic target of rapamycin (mTOR) and ryanodine receptor (RyR) signaling pathways regulate fundamental processes of neurodevelopment, and genetic mutations within these pathways have been linked to neurodevelopmental disorders. While previous studies have established that these signaling molecules are expressed in developing zebrafish, a detailed characterization of the ontogenetic profile of these signaling molecules is lacking. Thus, we evaluated the spatiotemporal expression of key transcripts in mTOR and RyR signaling pathways in wildtype zebrafish at 24, 72 and 120 hours post fertilization (hpf). We further determined whether transcriptional profiles of a subset of genes in both pathways were altered by exposure to PCB 95 (2,2′,3,5′,6-pentachlorobiphenyl), a pervasive environmental contaminant known to cause developmental neurotoxicity in mammalian systems via RyR-dependent mechanisms. Quantitative PCR revealed that transcription generally increased across development. Genes in the signaling pathway upstream of the mTORC1 complex, and the RyR-paralogs, ryr2a and ryr3, were robustly upregulated, and in situ hybridization of ryr3 coincided with a transcriptional shift from muscle to neuronal tissue after 24 hpf. Static waterborne exposure to PCB 95 beginning at 6 hpf significantly altered transcription of genes in both pathways. These changes were concentration- and time-dependent, and included downregulation of rptor, a member of the mTORC1 complex, at both 72 and 120 hpf, and increased transcript levels of the RyR paralog ryr2b and downstream target of RyR signaling, Wingless-type 2ba (wnt2ba) at 72 hpf. The detailed transcriptomic profiling of key genes within these two signaling pathways provides a baseline for identifying other environmental factors that modify normal spatiotemporal expression patterns of mTOR and RyR signaling pathways in the developing zebrafish, as illustrated here for PCB 95.

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Section: Introductionmentioning

confidence: 99%

Transcriptomic profiling of mTOR and ryanodine receptor signaling molecules in developing zebrafish in the absence and presence of PCB 95

Frank

Miller

Connon

et al. 2017

PeerJ

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Emerging pathways driving early synaptic pathology in Alzheimer's disease

Briggs

Chakroborty

Stutzmann

2017

Biochemical and Biophysical Research Communications

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The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function. With regard to the latter, the recent disappointing series of failed Phase III clinical trials targeting Aβ and APP processing, in concert with poor association between brain Aβ levels and cognitive function, have led many to call for a re-evaluation of the primacy of the amyloid cascade hypothesis. In this review, we integrate new insights into one of the earliest described signaling abnormalities in AD pathogenesis, namely intracellular Ca2+ signaling disruptions, and focus on its role in driving synaptic deficits – which is the feature that does correlate with AD-associated memory loss. Excess Ca2+release from intracellular stores such as the endoplasmic reticulum (ER) has been well-described in cellular and animal models of AD, as well as human patients, and here we expand upon recent developments in ER-localized release channels such as the IP3R and RyR, and the recent emphasis on RyR2. Consistent with ER Ca2+ mishandling in AD are recent findings implicating aspects of SOCE, such as STIM2 function, and TRPC3 and TRPC6 levels. Other Ca2+-regulated organelles important in signaling and protein handling are brought into the discussion, with new perspectives on lysosomal regulation. These early signaling abnormalities are discussed in the context of synaptic pathophysiology and disruptions in synaptic plasticity with a particular emphasis on short-term plasticity deficits. Overall, we aim to update and expand the list of early neuronal signaling abnormalities implicated in AD pathogenesis, identify specific channels and organelles involved, and link these to proximal synaptic impairments driving the memory loss in AD. This is all within the broader goal of identifying novel therapeutic targets to preserve cognitive function in AD.

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Dysregulation of Intracellular Calcium Signaling in Alzheimer's Disease

Попугаева

Pchitskaya

Bezprozvanny

2018

Antioxidants & Redox Signaling

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There is a need to determine whether AD is a syndrome with one critical signaling pathway that initiates pathology, or it is a disorder with many different signaling pathways that are disrupted simultaneously or one after each other. It is necessary to validate applicability of nSOCE-activating therapy for the development of anti-AD medication. There is an experimental correlation between downregulated nSOCE and disrupted postsynaptic contacts in AD mouse models. Signaling mechanisms downstream of nSOCE which are responsible for the regulation of stability of postsynaptic contacts have to be discovered. That will bring new targets for the development of AD-preventing therapies. Antioxid. Redox Signal. 29, 1176-1188.

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Regulation of ryanodine receptor-mediated calcium signaling by presenilins

Cited by 6 publications

References 21 publications

Transcriptomic profiling of mTOR and ryanodine receptor signaling molecules in developing zebrafish in the absence and presence of PCB 95

Transcriptomic profiling of mTOR and ryanodine receptor signaling molecules in developing zebrafish in the absence and presence of PCB 95

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Dysregulation of Intracellular Calcium Signaling in Alzheimer's Disease

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