Contribution of NAADP to Glutamate-Evoked Changes in Ca2+ Homeostasis in Mouse Hippocampal Neurons

Hermann, Julia; Bender, Melanie; Schumacher, Dagmar; Woo, Marcel S; Shaposhnykov, Artem; Rosenkranz, Sina Cathérine; Kuryshev, Vladimir; Meier, Chris; Guse, Andreas H.; Friese, Manuel A.; Freichel, Marc; Tsvilovskyy, Volodymyr

doi:10.3389/fcell.2020.00496

Cited by 10 publications

(4 citation statements)

References 53 publications

(103 reference statements)

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“…TPCs contribute to neuronal homeostasis [97]. The neurotransmitter, glutamate, uses an NAADP pathway to drive Ca 2+ signals [98][99][100] which in turn can drive neuronal autophagy via TPC1/2 [96]. TPCs are important for memory and long-term potentiation [99,101], neuroprotection [98] and axonal/neurite extension [72,102].…”

Section: Tpcs and Healthmentioning

confidence: 99%

Two-pore channels: going with the flows

Morgan

Martucci

Davis

et al. 2022

Biochemical Society Transactions

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In recent years, our understanding of the structure, mechanisms and functions of the endo-lysosomal TPC (two-pore channel) family have grown apace. Gated by the second messengers, NAADP and PI(3,5)P2, TPCs are an integral part of fundamental signal-transduction pathways, but their array and plasticity of cation conductances (Na+, Ca2+, H+) allow them to variously signal electrically, osmotically or chemically. Their relative tissue- and organelle-selective distribution, together with agonist-selective ion permeabilities provides a rich palette from which extracellular stimuli can choose. TPCs are emerging as mediators of immunity, cancer, metabolism, viral infectivity and neurodegeneration as this short review attests.

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Section: Tpcs and Healthmentioning

confidence: 99%

Two-pore channels: going with the flows

Morgan

Martucci

Davis

et al. 2022

Biochemical Society Transactions

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“…However, to our knowledge our study provides the first direct evidence that the secretory granules have an active role in receptor-evoked and NAADP-mediated Ca 2+ signaling and may control their own exocytosis. The NAADP pathway and TPC1/2 are present in other secretory cells, including neurons, where they are required for Ca 2+ signaling and cell function by glutamate receptors ( 46 , 47 ). It needs further investigation whether OCaR1 has a similar role for Ca 2+ oscillations and exocytosis in other types of secretory cells.…”

Section: Discussionmentioning

confidence: 99%

OCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca2+ release, exocytosis, and pancreatic tissue damage

Tsvilovskyy,

Ottenheijm,

Kriebs

et al. 2024

Journal of Clinical Investigation

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Regulated exocytosis is initiated by increased Ca 2+ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at rest. Here we showed that exocytosis of zymogen granules in acinar cells was driven by Ca 2+ directly released from acidic Ca 2+ stores including secretory granules through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded by Tmem63a ) as an o rganellar Ca 2+ r egulator protein integral to the membrane of secretory granules that controlled Ca 2+ release via inhibition of TPC1 and TPC2 currents. Deletion of OCaR1 led to extensive Ca 2+ release from NAADP-responsive granules under basal conditions as well as upon stimulation of GPCR receptors. Moreover, OCaR1 deletion exacerbated the disease phenotype in murine models of severe and chronic pancreatitis. Our findings showed OCaR1 as a gatekeeper of Ca 2+ release that endows NAADP-sensitive secretory granules with an autoregulatory mechanism preventing uncontrolled exocytosis and pancreatic tissue damage.

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“…To date, most of the physiological functions of TPC2 have been related to the Ca 2+ signaling and lysosomal processes it maintains. In neurons, the neurotransmitter glutamate uses NAADP to turn on Ca 2+ signaling, which further drives autophagy through TPC2 to maintain neuronal homeostasis and function [115]. Defects in TPC2 may lead to neurodegeneration, resulting in AD and PD [116].…”

Section: Tpcsmentioning

confidence: 99%

Advances in Drug Discovery Targeting Lysosomal Membrane Proteins

et al. 2023

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Lysosomes are essential organelles of eukaryotic cells and are responsible for various cellular functions, including endocytic degradation, extracellular secretion, and signal transduction. There are dozens of proteins localized to the lysosomal membrane that control the transport of ions and substances across the membrane and are integral to lysosomal function. Mutations or aberrant expression of these proteins trigger a variety of disorders, making them attractive targets for drug development for lysosomal disorder-related diseases. However, breakthroughs in R&D still await a deeper understanding of the underlying mechanisms and processes of how abnormalities in these membrane proteins induce related diseases. In this article, we summarize the current progress, challenges, and prospects for developing therapeutics targeting lysosomal membrane proteins for the treatment of lysosomal-associated diseases.

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Contribution of NAADP to Glutamate-Evoked Changes in Ca2+ Homeostasis in Mouse Hippocampal Neurons

Cited by 10 publications

References 53 publications

Two-pore channels: going with the flows

Two-pore channels: going with the flows

OCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca2+ release, exocytosis, and pancreatic tissue damage

Advances in Drug Discovery Targeting Lysosomal Membrane Proteins

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