Relative Role of Akt, ERK and CREB in Alcohol-Induced Microglia P2X4R Receptor Expression

Gofman, Larisa; Fernandes, Natália C.; Potula, Raghava

doi:10.1093/alcalc/agw009

Cited by 20 publications

(21 citation statements)

References 44 publications

(61 reference statements)

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“…It is also known that in more drastic cases, alcohol can even induce apoptosis in microglia [72] . Many of these effects can be attributed to the alcohol-induced expression of P2X4 in microglial cells, and involve the inhibition of the AKT and ERK cascades [73] . This increase in P2X4 is observed at both mRNA and protein levels [71] .…”

Section: Functional Roles Of P2x4 In the Nervous Systemmentioning

confidence: 99%

P2X4: A fast and sensitive purinergic receptor

et al. 2017

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Extracellular nucleotides have been recognized as important mediators of activation, triggering multiple responses via plasma membrane receptors known as P2 receptors. P2 receptors comprise P2X ionotropic receptors and G protein-coupled P2Y receptors. P2X receptors are expressed in many tissues, where they are involved in a number of functions including synaptic transmission, muscle contraction, platelet aggregation, inflammation, macrophage activation, differentiation and proliferation, neuropathic and inflammatory pain. P2X4 is one of the most sensitive purinergic receptors (at nanomolar ATP concentrations), about one thousand times more than the archetypal P2X7. P2X4 is widely expressed in central and peripheral neurons, in microglia, and also found in various epithelial tissues and endothelial cells. It localizes on the plasma membrane, but also in intracellular compartments. P2X4 is preferentially localized in lysosomes, where it is protected from proteolysis by its glycosylation. High ATP concentration in the lysosomes does not activate P2X4 at low pH; P2X4 gets activated by intra-lysosomal ATP only in its fully dissociated tetra-anionic form, when the pH increases to 7.4. Thus, P2X4 is functioning as a Ca2+-channel after the fusion of late endosomes and lysosomes. P2X4 modulates major neurotransmitter systems and regulates alcohol-induced responses in microglia. P2X4 is one of the key receptors mediating neuropathic pain. However, injury-induced upregulation of P2X4 expression is gender dependent and plays a key role in pain difference between males and females. P2X4 is also involved in inflammation. Extracellular ATP being a pro-inflammatory molecule, P2X4 can trigger inflammation in response to high ATP release. It is therefore involved in multiple pathologies, like post-ischemic inflammation, rheumatoid arthritis, airways inflammation in asthma, neurodegenerative diseases and even metabolic syndrome. Although P2X4 remains poorly characterized, more studies are needed as it is likely to be a potential therapeutic target in these multiple pathologies.

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Section: Functional Roles Of P2x4 In the Nervous Systemmentioning

confidence: 99%

P2X4: A fast and sensitive purinergic receptor

et al. 2017

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“…It is now known that mutant p53 proteins not only lost their transcriptional function (loss of function), but also commonly obtain new function (gain of function). 7 For instance, p53-R175H exhibits a gain of oncogenic function in driving cell migration and invasion. 4 , 8 Studies from animal models have confirmed that mice bearing a mutant p53 allele show more aggressive and metastatic tumor than p53 null.…”

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confidence: 99%

p53-R273H upregulates neuropilin-2 to promote cell mobility and tumor metastasis

Sun

et al. 2017

Cell Death Dis

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Mounting evidence indicates that hotspot p53 mutant proteins often possess gain-of-function property in promoting cell mobility and tumor metastasis. However, the molecular mechanisms are not totally understood. In this study, we demonstrate that the hotspot mutation, p53-R273H, promotes cell migration, invasion in vitro and tumor metastasis in vivo. p53-R273H significantly represses expression of DLX2, a homeobox protein involved in cell proliferation and pattern formation. We show that p53-R273H-mediated DLX2 repression leads to upregulation of Neuropilin-2 (NRP2), a multifunctional co-receptor involved in tumor initiation, growth, survival and metastasis. p53-R273H-induced cell mobility is effectively suppressed by DLX2 expression. Furthermore, knockdown of NRP2 significantly inhibits p53-R273H-induced tumor metastasis in xenograft mouse model. Together, these results reveal an important role for DLX2-NRP2 in p53-R273H-induced cell mobility and tumor metastasis.

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“…137 Supporting evidences indicate that P2X4 receptors physically couple with GABA A receptors as well as with the P2X 2 receptors and this cross talk may play a role in regulating synaptic signaling and plasticity of neurons. 160 Alcohol abuse is known to enhance neuroinflammation through P2X 4 Rs activation 161 and there are suggestions of implication of P2X 4 Rs in tolerance to morphine and hyperalgesia induction by morphine. 161,162 P2X 4 receptors are upregulated in TBI 6 , in acute experimental encephalomyelitis (EAE) rodent model of multiple sclerosis 17 and following hypoxia and ischemia events.…”

Section: P2x 4 Receptor and Functions In The Cnsmentioning

confidence: 99%

“…160 Alcohol abuse is known to enhance neuroinflammation through P2X 4 Rs activation 161 and there are suggestions of implication of P2X 4 Rs in tolerance to morphine and hyperalgesia induction by morphine. 161,162 P2X 4 receptors are upregulated in TBI 6 , in acute experimental encephalomyelitis (EAE) rodent model of multiple sclerosis 17 and following hypoxia and ischemia events. 163 In neurons, P2X 4 R has shown to stimulate activation of the inflammasome caspase-1 resulting in cytokines IL-18 and IL-b release, and in P2X 4 R knockout mice, impaired inflammasome signaling was reported to couple to the reduction of IL-b level.…”

Section: P2x 4 Receptor and Functions In The Cnsmentioning

confidence: 99%

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

Zarrinmayeh

Territo

2020

Mol Imaging

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Purinergic receptors play important roles in central nervous system (CNS). These receptors are involved in cellular neuroinflammatory responses that regulate functions of neurons, microglial and astrocytes. Based on their endogenous ligands, purinergic receptors are classified into P1 or adenosine, P2X and P2Y receptors. During brain injury or under pathological conditions, rapid diffusion of extracellular adenosine triphosphate (ATP) or uridine triphosphate (UTP) from the damaged cells, promote microglial activation that result in the changes in expression of several of these receptors in the brain. Imaging of the purinergic receptors with selective Positron Emission Tomography (PET) radioligands has advanced our understanding of the functional roles of some of these receptors in healthy and diseased brains. In this review, we have accumulated a list of currently available PET radioligands of the purinergic receptors that are used to elucidate the receptor functions and participations in CNS disorders. We have also reviewed receptors lacking radiotracer, laying the foundation for future discoveries of novel PET radioligands to reveal these receptors roles in CNS disorders.

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Relative Role of Akt, ERK and CREB in Alcohol-Induced Microglia P2X4R Receptor Expression

Abstract: These findings provide important clues to the underlying mechanism of purinoceptors in alcohol-induced microglia immune suppression.

Cited by 20 publications

References 44 publications

P2X4: A fast and sensitive purinergic receptor

P2X4: A fast and sensitive purinergic receptor

p53-R273H upregulates neuropilin-2 to promote cell mobility and tumor metastasis

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

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