Quantifying Ca2+ Current and Permeability in ATP-gated P2X7 Receptors

Liang, Xin; Samways, Damien S. K.; Wolf, Kyle J.; Bowles, Elizabeth; Richards, J. P.; Bruno, Jonathan; Dutertre, Sébastien; DiPaolo, Richard J.; Egan, Terrance M.

doi:10.1074/jbc.m114.627810

Cited by 40 publications

(37 citation statements)

References 97 publications

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“…More central to our project was the finding that the two mutant constructs with altered C-termini (X7-X7-X2 and X2-X7-X2) showed significantly less facilitation than the wild-type receptor (see Table 1). Taken together, these results support the contention that facilitation of P2X7R current requires a fulllength native C-terminal tail (Yan et al, 2008(Yan et al, , 2010Liang et al, 2015).…”

Section: Resultssupporting

confidence: 83%

HSP90 Regulation of P2X7 Receptor Function Requires an Intact Cytoplasmic C-Terminus

et al. 2016

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P2X7 receptors (P2X7Rs) are ATP-gated ion channels that display the unusual property of current facilitation during long applications of agonists. Here we show that facilitation disappears in chimeric P2X7Rs containing the C-terminus of the P2X2 receptor (P2X2R), and in a truncated P2X7R missing the cysteine-rich domain of the C-terminus. The chimeric and truncated receptors also show an apparent decreased permeability to N-methyl-D-glucamine 1 (NMDG 1 ). The effects of genetic modification of the C-terminus on NMDG 1 permeability were mimicked by preapplication of the HSP90 antagonist geldanamycin to the wild-type receptor. Further, the geldanamycin decreased the shift in the reversal potential of the ATPgated current measured under bi-ionic NMDG 1 /Na 1 condition without affecting the ability of the long application of agonist to facilitate current amplitude. Taken together, the results suggest that HSP90 may be essential for stabilization and function of P2X7Rs through an action on the cysteine-rich domain of the cytoplasmic the C-terminus.

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Section: Resultssupporting

confidence: 83%

HSP90 Regulation of P2X7 Receptor Function Requires an Intact Cytoplasmic C-Terminus

et al. 2016

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“…2,3,5 In addition, splice variants have been shown to display different pharmacological properties. 111 Neuronal P2XRs in the inner and outer retina contribute to visual processing, as well as cell death in retinal ganglia. P2X2R is present in the trigeminal ganglion sensory neurons and ciliary body.…”

Section: P2xr Modulators As Drug Targets In the Eyementioning

confidence: 99%

Ocular Purine Receptors as Drug Targets in the Eye

Civan

2016

Journal of Ocular Pharmacology and Therapeutics

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Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A 1 , A 2A , and A 3 . An A 1 AR agonist is in clinical trials for glaucoma, A 2A AR reduces neuroinflammation, A 3 AR protects retinal ganglion cells from apoptosis, and both A 3 AR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y 2 and P2Y 6 , lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.

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“…It has been known that the cation permeability by P2X receptor activation were modulated by divalent cations as “Ca 2+ dependent block” (Jarvis and Khakh, 2009; Kasuya et al, 2016), in which the ion permeability of P2X receptors are inhibited by the extracellular Ca 2+ in a concentration-dependent manner. The Ca 2+ dependent block for P2X receptors was also well-described in P2X 7 receptors (Yan et al, 2011; Liang et al, 2015). When we removed extracellular Ca 2+ from the standard ECS (Ca 2+ -free ECS), the amplitude of K + -ATP-induced currents augmented compared to those in the standard ECS.…”

Section: Discussionmentioning

confidence: 66%

Ionotropic P2X ATP Receptor Channels Mediate Purinergic Signaling in Mouse Odontoblasts

et al. 2017

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ATP modulates various functions in the dental pulp cells, such as intercellular communication and neurotransmission between odontoblasts and neurons, proliferation of dental pulp cells, and odontoblast differentiation. However, functional expression patterns and their biophysical properties of ionotropic ATP (P2X) receptors (P2X1–P2X7) in odontoblasts were still unclear. We examined these properties of P2X receptors in mouse odontoblasts by patch-clamp recordings. K+-ATP, nonselective P2X receptor agonist, induced inward currents in odontoblasts in a concentration-dependent manner. K+-ATP-induced currents were inhibited by P2X4 and P2X7 selective inhibitors (5-BDBD and KN62, respectively), while P2X1 and P2X3 inhibitors had no effects. P2X7 selective agonist (BzATP) induced inward currents dose-dependently. We could not observe P2X1, 2/3, 3 selective agonist (αβ-MeATP) induced currents. Amplitudes of K+-ATP-induced current were increased in solution without extracellular Ca2+, but decreased in Na+-free extracellular solution. In the absence of both of extracellular Na+ and Ca2+, K+-ATP-induced currents were completely abolished. K+-ATP-induced Na+ currents were inhibited by P2X7 inhibitor, while the Ca2+ currents were sensitive to P2X4 inhibitor. These results indicated that odontoblasts functionally expressed P2X4 and P2X7 receptors, which might play an important role in detecting extracellular ATP following local dental pulp injury.

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Quantifying Ca2+ Current and Permeability in ATP-gated P2X7 Receptors

Cited by 40 publications

References 97 publications

HSP90 Regulation of P2X7 Receptor Function Requires an Intact Cytoplasmic C-Terminus

HSP90 Regulation of P2X7 Receptor Function Requires an Intact Cytoplasmic C-Terminus

Ocular Purine Receptors as Drug Targets in the Eye

Ionotropic P2X ATP Receptor Channels Mediate Purinergic Signaling in Mouse Odontoblasts

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