Channel-mediated ATP release in the nervous system

Dale, Nicholas; Butler, Jack L.; Dospinescu, Valentin-Mihai; Nijjar, Sarbjit

doi:10.1016/j.neuropharm.2023.109435

Cited by 7 publications

(4 citation statements)

References 154 publications

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“…The release of ATP into the extracellular environment can occur through dying cells as well as inflammatory signaling. 70–72 Previous work examining human brain AD neuropathology found elevated P2RX7 expression. Specifically, P2RX7 is upregulated on microglia near amyloid-beta plaques.…”

Section: Discussionmentioning

confidence: 99%

IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells

Heavener,

Kabra,

Yidenk

et al. 2024

Preprint

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The immune system has a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades and its expression is upregulated in Alzheimer′s disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding amyloid-beta plaques in the brain. While P2RX7 is thought to play a role in neurodegenerative diseases, how it modulates pathology and disease progression is not well understood. Here, we utilize a human monocyte-derived microglia-like cell (MDMi) model to interrogate P2RX7 activation and downstream consequences on microglia function. By using MDMi derived from human donors, we can examine how human donor variation impacts microglia function. We assessed P2RX7-driven IL1β and IL18 production and amyloid-beta peptide 1-42 (Aβ1-42) uptake levels. Our results show that ATP-stimulation of MDMi triggers upregulation of IL1β and IL18 expression. This upregulation of cytokine gene expression is blocked with the A740003 P2RX7 antagonist. We find that high extracellular ATP conditions also reduced MDMi capacity for Aβ1-42 uptake, and this loss of function is prevented through A740003 inhibition of P2RX7. In addition, pretreatment of MDMi with IL-1RA limited ATP-driven IL1β and IL18 gene expression upregulation, indicating that ATP immunomodulation of P2RX7 is IL-1R dependent. Aβ1-42 uptake was higher with IL-1RA pretreatment compared to ATP treatment alone, suggesting P2RX7 regulates phagocytic engulfment through IL-1 signaling. Overall, our results demonstrate that P2RX7 is a key response protein for high extracellular ATP in human microglia-like cells, and its function can be modulated by IL-1 signaling. This work opens the door to future studies examining anti-IL-1 biologics to increase the clearance of amyloid-beta.

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Section: Discussionmentioning

confidence: 99%

IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells

Heavener,

Kabra,

Yidenk

et al. 2024

Preprint

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“…Astrocytes can also release ATP via other pathways, including pannexins (Suadicani et al, 2012), P2X7 receptor (Sylvia et al, 2006), VRAC (Fujii et al, 2017), CALHM2 (Ma et al, 2018), and maxi-anion channels (Liu et al, 2008). There are excellent reviews on channel-mediated ATP release mechanisms (Dale et al, 2023).…”

Section: Atp Release From Astrocytesmentioning

confidence: 99%

“…However, recent findings suggest that adenosine is also derived from ATP released from astrocytes and that microglia play a major role in the conversion of ATP to adenosine. ATP is released from almost every cell type via distinct pathways ( Taruno, 2018 ; Dale et al, 2023 ). Therefore, purinergic signaling is far more complex than previously thought.…”

Section: Introductionmentioning

confidence: 99%

Extracellular ATP/adenosine dynamics in the brain and its role in health and disease

Shigetomi,

Sakai,

Koizumi

2024

Front. Cell Dev. Biol.

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Extracellular ATP and adenosine are neuromodulators that regulate numerous neuronal functions in the brain. Neuronal activity and brain insults such as ischemic and traumatic injury upregulate these neuromodulators, which exert their effects by activating purinergic receptors. In addition, extracellular ATP/adenosine signaling plays a pivotal role in the pathogenesis of neurological diseases. Virtually every cell type in the brain contributes to the elevation of ATP/adenosine, and various mechanisms underlying this increase have been proposed. Extracellular adenosine is thought to be mainly produced via the degradation of extracellular ATP. However, adenosine is also released from neurons and glia in the brain. Therefore, the regulation of extracellular ATP/adenosine in physiological and pathophysiological conditions is likely far more complex than previously thought. To elucidate the complex mechanisms that regulate extracellular ATP/adenosine levels, accurate methods of assessing their spatiotemporal dynamics are needed. Several novel techniques for acquiring spatiotemporal information on extracellular ATP/adenosine, including fluorescent sensors, have been developed and have started to reveal the mechanisms underlying the release, uptake and degradation of ATP/adenosine. Here, we review methods for analyzing extracellular ATP/adenosine dynamics as well as the current state of knowledge on the spatiotemporal dynamics of ATP/adenosine in the brain. We focus on the mechanisms used by neurons and glia to cooperatively produce the activity-dependent increase in ATP/adenosine and its physiological and pathophysiological significance in the brain.

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“…Broadly, mechanisms of intermittent ATP release can be the result of (1) cell damage or cell death (e.g., complement activation and MAC deposition, osmotic swelling, ischemia, inflammation, or apoptosis leading to the passive leakage of ATP from cells), (2) vesicular release, or (3) channel-mediated release ( Bulanova and Bulfone-Paus, 2010 ). However, sustained ATP release which is likely the ATP release of pathophysiological significance can also result from a multiplicity of pathways ( Lazarowski et al, 2003 ; Dale et al, 2023 ; Di Virgilio et al, 2023 ; Shinozaki et al, 2023 ). Within the outer retina, several processes that contribute to AMD pathogenesis lead to ATP release ( Figure 2 ).…”

Section: Mechanisms Of Atp Releasementioning

confidence: 99%

Purinergic signaling via P2X receptors and mechanisms of unregulated ATP release in the outer retina and age-related macular degeneration

Molcak,

Jiang,

Campbell

et al. 2023

Front. Neurosci.

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Age-related macular degeneration (AMD) is a chronic and progressive inflammatory disease of the retina characterized by photoceptor loss and significant central visual impairment due to either choroidal neovascularization or geographic atrophy. The pathophysiology of AMD is complex and multifactorial, driven by a combination of modifiable and non-modifiable risk factors, molecular mechanisms, and cellular processes that contribute to overall disease onset, severity, and progression. Unfortunately, due to the structural, cellular, and pathophysiologic complexity, therapeutic discovery is challenging. While purinergic signaling has been investigated for its role in the development and treatment of ocular pathologies including AMD, the potential crosstalk between known contributors to AMD, such as the complement cascade and inflammasome activation, and other biological systems, such as purinergic signaling, have not been fully characterized. In this review, we explore the interactions between purinergic signaling, ATP release, and known contributors to AMD pathogenesis including complement dysregulation and inflammasome activation. We begin by identifying what is known about purinergic receptors in cell populations of the outer retina and potential sources of extracellular ATP required to trigger purinergic receptor activation. Next, we examine evidence in the literature that the purinergic system accelerates AMD pathogenesis leading to apoptotic and pyroptotic cell death in retinal cells. To fully understand the potential role that purinergic signaling plays in AMD, more research is needed surrounding the expression, distribution, functions, and interactions of purinergic receptors within cells of the outer retina as well as potential crosstalk with other systems. By determining how these processes are affected in the context of purinergic signaling, it will improve our understanding of the mechanisms that drive AMD pathogenesis which is critical in developing treatment strategies that prevent or slow progression of the disease.

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Channel-mediated ATP release in the nervous system

Cited by 7 publications

References 154 publications

IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells

IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells

Extracellular ATP/adenosine dynamics in the brain and its role in health and disease

Purinergic signaling via P2X receptors and mechanisms of unregulated ATP release in the outer retina and age-related macular degeneration

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