ATP-Gated P2X7 Receptors Require Chloride Channels To Promote Inflammation in Human Macrophages

Janks, Laura; Sprague, Randy S.; Egan, Terrance M.

doi:10.4049/jimmunol.1801101

Cited by 39 publications

(48 citation statements)

References 108 publications

(130 reference statements)

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“…Based on findings in osteoblasts, it was proposed that P2X7 activation leads via PLD and PLA2 activation to LPA, and LPA, by activation of the LPA receptor (a GPCR), activates Rho (Panupinthu et al, 2007). Involvement of PLA2 activation in addition to an undefined Cl – channel in blebbing is supported by a recent study on macrophages (Janks et al, 2019).…”

Section: P2x7 Mediated Signaling Pathwaysmentioning

confidence: 62%

“…P2X7-mediated activation of cPLA2 and iPLA2 has been reported in immune and epithelial cells (Alzola et al, 1998; Chaib et al, 2000; Andrei et al, 2004; Kahlenberg and Dubyak, 2004; Garcia-Marcos et al, 2006b; Costa-Junior et al, 2011) and has been associated with various downstream effects such as PLD activation, kallikrein secretion, bioactive lipid generation, and pore formation as well as IL-1β processing, blebbing, and PS-flip (Garcia-Marcos et al, 2006b; Anrather et al, 2011; Costa-Junior et al, 2011; Norris et al, 2014; Wan et al, 2014; Alarcon-Vila et al, 2019; Janks et al, 2019). Janks et al (2019) recently reported an involvement of undefined chloride channels downstream of PLA2 in some of these processes. The mechanism of PLA2 activation by P2X7 remains unclear but was suggested to involve MAP kinases, P-I4 kinase/PIP2 (Garcia-Marcos et al, 2006b; Wan et al, 2014) and/or n-SMase activation in lipid rafts (Garcia-Marcos et al, 2006a).…”

Section: P2x7 Mediated Signaling Pathwaysmentioning

confidence: 99%

“…While this could be attributed to single aa differences in the ligand-binding ectodomain of rat and mouse P2X7 (Young et al, 2007), a positive effect of the intracellular C-terminus on BzATP potency was shown in P2X7 chimeras, in which the human P2X7 C-terminus was replaced by the respective rat sequence (Rassendren et al, 1997). Likewise, sensitivity to divalent cations, dye-uptake efficiency and selectivity, and current kinetics largely differ between human and rodent isoforms and also between different cell types (Rassendren et al, 1997; Hibell et al, 2001; Janks et al, 2019) with the human and mouse isoforms being less efficient in dye uptake. However, despite these differences, the principal effects of P2X7 activation, such as dye uptake, interleukine-1β (IL-1β) release, phosphatidylserine-flip (PS)-flip, and blebbing appear to be present in all isoforms.…”

Section: Introductionmentioning

confidence: 99%

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P2X7 Interactions and Signaling – Making Head or Tail of It

Kopp¹,

Krautloher²,

Ramírez-Fernández³

et al. 2019

Front. Mol. Neurosci.

183

153

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Extracellular adenine nucleotides play important roles in cell–cell communication and tissue homeostasis. High concentrations of extracellular ATP released by dying cells are sensed as a danger signal by the P2X7 receptor, a non-specific cation channel. Studies in P2X7 knockout mice and numerous disease models have demonstrated an important role of this receptor in inflammatory processes. P2X7 activation has been shown to induce a variety of cellular responses that are not usually associated with ion channel function, for example changes in the plasma membrane composition and morphology, ectodomain shedding, activation of lipases, kinases, and transcription factors, as well as cytokine release and apoptosis. In contrast to all other P2X family members, the P2X7 receptor contains a long intracellular C-terminus that constitutes 40% of the whole protein and is considered essential for most of these effects. So far, over 50 different proteins have been identified to physically interact with the P2X7 receptor. However, few of these interactions have been confirmed in independent studies and for the majority of these proteins, the interaction domains and the physiological consequences of the interactions are only poorly described. Also, while the structure of the P2X7 extracellular domain has recently been resolved, information about the organization and structure of its C-terminal tail remains elusive. After shortly describing the structure and assembly of the P2X7 receptor, this review gives an update of the identified or proposed interaction domains within the P2X7 C-terminus, describes signaling pathways in which this receptor has been involved, and provides an overlook of the identified interaction partners.

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Section: P2x7 Mediated Signaling Pathwaysmentioning

confidence: 62%

Section: P2x7 Mediated Signaling Pathwaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

P2X7 Interactions and Signaling – Making Head or Tail of It

Kopp¹,

Krautloher²,

Ramírez-Fernández³

et al. 2019

Front. Mol. Neurosci.

183

153

View full text Add to dashboard Cite

show abstract

“…In macrophages, P2X7Rs require anion channels to promote inflammation [ 50 ]. ATP is secreted by macrophages and microglia via volume-regulated anion channels (VRACs) [ 51 , 52 ], which may activate purinergic receptors.…”

Section: Resultsmentioning

confidence: 99%

Dissection of P2X4 and P2X7 Receptor Current Components in BV-2 Microglia

Trang

Schmalzing

Müller

et al. 2020

IJMS

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Microglia cells represent the immune system of the central nervous system. They become activated by ATP released from damaged and inflamed tissue via purinergic receptors. Ionotropic purinergic P2X4 and P2X7 receptors have been shown to be involved in neurological inflammation and pain sensation. Whether the two receptors assemble exclusively as homotrimers or also as heterotrimers is still a matter of debate. We investigated the expression of P2X receptors in BV-2 microglia cells applying the whole-cell voltage-clamp technique. We dissected P2X4 and P2X7 receptor-mediated current components by using specific P2X4 and P2X7 receptor blockers and by their characteristic current kinetics. We found that P2X4 and P2X7 receptors are activated independently from each other, indicating that P2X4/P2X7 heteromers are not of functional significance in these cells. The pro-inflammatory mediators lipopolysaccharide and interferon γ, if applied in combination, upregulated P2X4, but not P2X7 receptor-dependent current components also arguing against phenotypically relevant heteromerization of P2X4 and P2X7 receptor subunits.

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“…However, this was later shown to be independent of the entry of cationic molecules via the receptor-channel and rather caused by a Ca 2+ /calmodulin-dependent current facilitation through some P2X7R orthologs (rat, but not human) (Roger et al, 2010) or the secondary activation of a chloride current e.g. in macrophages (Janks et al, 2019).…”

Section: P2x7 Receptormentioning

confidence: 99%

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

Illéš

Müller

Jacobson

et al. 2020

British J Pharmacology

221

202

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The known seven mammalian receptor (R) subunits (P2X1-7) form cationic channels gated by ATP. Three subunits compose a receptor-channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1, TM2), intracellular Nand C-termini, and a bulky extracellular loop. Crystallization allowed the identification of the 3D-structure and gating cycle of P2XRs. The agonist binding pocket is located at the intersection of two neighboring subunits. In addition to the mammalian P2XRs their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2XR subtypes are not available, but medicinal chemistry supplied a range of subtype selective antagonists, as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2XRs, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7).

show abstract

ATP-Gated P2X7 Receptors Require Chloride Channels To Promote Inflammation in Human Macrophages

Cited by 39 publications

References 108 publications

P2X7 Interactions and Signaling – Making Head or Tail of It

P2X7 Interactions and Signaling – Making Head or Tail of It

Dissection of P2X4 and P2X7 Receptor Current Components in BV-2 Microglia

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

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