International Journal of Molecular Sciences

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3 pages, 166 KiB

Open AccessEditorial

Purinergic P2 Receptors: Structure and Function 2.0

by Hana Zemkova

Int. J. Mol. Sci. 2023, 24(6), 5462; https://doi.org/10.3390/ijms24065462 - 13 Mar 2023

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Abstract

This Special Issue of the International Journal of Molecular Sciences (IJMS) is a direct continuation of the previous Special Issue of this journal, entitled “Purinergic P2 Receptors: Structure and Function” https://www [...] Full article

(This article belongs to the Special Issue Purinergic P2 Receptors: Structure and Function 2.0)

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15 pages, 4950 KiB

Open AccessArticle

P2X4 Receptors Mediate Ca²⁺ Release from Lysosomes in Response to Stimulation of P2X7 and H₁ Histamine Receptors

by Sin-Lih Tan, Muruj Barri, Peace Atakpa-Adaji, Colin W. Taylor, Ewan St. John Smith and Ruth D. Murrell-Lagnado

Int. J. Mol. Sci. 2021, 22(19), 10492; https://doi.org/10.3390/ijms221910492 - 28 Sep 2021

Cited by 6 | Viewed by 2641

Abstract

The P2X4 purinergic receptor is targeted to endolysosomes, where it mediates an inward current dependent on luminal ATP and pH. Activation of P2X4 receptors was previously shown to trigger lysosome fusion, but the regulation of P2X4 receptors and their role in lysosomal Ca [...] Read more.

The P2X4 purinergic receptor is targeted to endolysosomes, where it mediates an inward current dependent on luminal ATP and pH. Activation of P2X4 receptors was previously shown to trigger lysosome fusion, but the regulation of P2X4 receptors and their role in lysosomal Ca²⁺ signaling are poorly understood. We show that lysosomal P2X4 receptors are activated downstream of plasma membrane P2X7 and H₁ histamine receptor stimulation. When P2X4 receptors are expressed, the increase in near-lysosome cytosolic [Ca²⁺] is exaggerated, as detected with a low-affinity targeted Ca²⁺ sensor. P2X4-dependent changes in lysosome properties were triggered downstream of P2X7 receptor activation, including an enlargement of lysosomes indicative of homotypic fusion and a redistribution of lysosomes towards the periphery of the cell. Lysosomal P2X4 receptors, therefore, have a role in regulating lysosomal Ca²⁺ release and the regulation of lysosomal membrane trafficking. Full article

(This article belongs to the Special Issue Purinergic P2 Receptors: Structure and Function 2.0)

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20 pages, 7528 KiB

Open AccessArticle

Analysis of Spatial and Temporal Distribution of Purinergic P2 Receptors in the Mouse Hippocampus

by Julian Lommen, Julika Detken, Katharina Harr, Charlotte von Gall and Amira A. H. Ali

Int. J. Mol. Sci. 2021, 22(15), 8078; https://doi.org/10.3390/ijms22158078 - 28 Jul 2021

Cited by 8 | Viewed by 1998

Abstract

ATP and other nucleotides are important glio-/neurotransmitters in the central nervous system. They bind to purinergic P2X and P2Y receptors that are ubiquitously expressed in various brain regions modulating various physiological and pathophysiological processes. P2X receptors are ligand-gated ion channels mediating excitatory postsynaptic [...] Read more.

ATP and other nucleotides are important glio-/neurotransmitters in the central nervous system. They bind to purinergic P2X and P2Y receptors that are ubiquitously expressed in various brain regions modulating various physiological and pathophysiological processes. P2X receptors are ligand-gated ion channels mediating excitatory postsynaptic responses whereas P2Y receptors are G protein-coupled receptors mediating slow synaptic transmission. A variety of P2X and P2Y subtypes with distinct neuroanatomical localization provide the basis for a high diversity in their function. There is increasing evidence that P2 receptor signaling plays a prominent role in learning and memory and thus, in hippocampal neuronal plasticity. Learning and memory are time-of-day-dependent. Moreover, extracellular ATP shows a diurnal rhythm in rodents. However, it is not known whether P2 receptors have a temporal variation in the hippocampus. This study provides a detailed systematic analysis on spatial and temporal distribution of P2 in the mouse hippocampus. We found distinct spatial and temporal distribution patterns of the P2 receptors in different hippocampal layers. The temporal distribution of P2 receptors can be segregated into two large time domains, the early to mid-day and the mid to late night. This study provides an important basis for understanding dynamic P2 purinergic signaling in the hippocampal glia/neuronal network. Full article

(This article belongs to the Special Issue Purinergic P2 Receptors: Structure and Function 2.0)

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12 pages, 1950 KiB

Open AccessArticle

Hybrid QM/MM Simulations Confirm Zn(II) Coordination Sphere That Includes Four Cysteines from the P2 × 4R Head Domain

by Francisco Andrés Peralta, J. Pablo Huidobro-Toro and Raúl Mera-Adasme

Int. J. Mol. Sci. 2021, 22(14), 7288; https://doi.org/10.3390/ijms22147288 - 7 Jul 2021

Cited by 1 | Viewed by 2009

Abstract

To ascertain the role of Zn(II) as an allosteric modulator on P2X4R, QM/MM molecular dynamic simulations were performed on the WT and two P2X4R mutants suggested by previous electrophysiological data to affect Zn(II) binding. The Gibbs free energy for the reduction of the [...] Read more.

To ascertain the role of Zn(II) as an allosteric modulator on P2X4R, QM/MM molecular dynamic simulations were performed on the WT and two P2X4R mutants suggested by previous electrophysiological data to affect Zn(II) binding. The Gibbs free energy for the reduction of the putative P2X4R Zn(II) binding site by glutathione was estimated at −22 kcal/mol. Simulations of the WT P2X4R head domain revealed a flexible coordination sphere dominated by an octahedral geometry encompassing C126, N127, C132, C149, C159 and a water molecule. The C132A mutation disrupted the metal binding site, leading to a coordination sphere with a majority of water ligands, and a displacement of the metal ion towards the solvent. The C132A/C159A mutant exhibited a tendency towards WT-like stability by incorporating the R148 backbone to the coordination sphere. Thus, the computational findings agree with previous experimental data showing Zn(II) modulation for the WT and C132A/C159A variants, but not for the C132A mutant. The results provide molecular insights into the nature of the Zn(II) modulation in P2X4R, and the effect of the C132A and C132A/C159A mutations, accounting for an elusive modulation mechanism possibly occurring in other extracellular or membrane protein. Full article

(This article belongs to the Special Issue Purinergic P2 Receptors: Structure and Function 2.0)

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12 pages, 1341 KiB

Open AccessArticle

Impact of P2X₇ Purinoceptors on Goblet Cell Function: Implications for Dry Eye

by Donald G. Puro

Int. J. Mol. Sci. 2021, 22(13), 6935; https://doi.org/10.3390/ijms22136935 - 28 Jun 2021

Cited by 10 | Viewed by 1949

Abstract

By providing ~70% of the eye’s refractive power, the preocular tear film is essential for optimal vision. However, its integrity is often jeopardized by environmental and pathologic conditions that accelerate evaporation and cause sight-impairing dry eye. A key adaptive response to evaporation-induced tear [...] Read more.

By providing ~70% of the eye’s refractive power, the preocular tear film is essential for optimal vision. However, its integrity is often jeopardized by environmental and pathologic conditions that accelerate evaporation and cause sight-impairing dry eye. A key adaptive response to evaporation-induced tear film hyperosmolarity is the reflex-triggered release of tear-stabilizing mucin from conjunctival goblet cells. Here, we review progress in elucidating the roles of ion channels in mediating this important exocytotic response. Much is now known about the modulatory impact of ATP-sensitive potassium channels, nonspecific cation channels and voltage-gated calcium channels. Recently, we discovered that during unremitting extracellular hyperosmolarity, P2X₇ receptor/channels also become activated and markedly impair goblet cell viability. However, our understanding of possible adaptive benefits of this P2X₇ activation remains limited. In the present study, we utilized high-temporal resolution membrane capacitance measurements to monitor the exocytotic activity of single goblet cells located in freshly excised rat conjunctiva. We now report that activation of P2X₇ purinoceptors boosts neural-evoked exocytosis and accelerates replenishment of mucin-filled granules after exocytotic depletion. Thus, P2X₇ activation exerts a yin-yang effect on conjunctival goblet cells: the high-gain benefit of enhancing the supply of tear-stabilizing mucin is implemented at the high-risk of endangering goblet cell survival. Full article

(This article belongs to the Special Issue Purinergic P2 Receptors: Structure and Function 2.0)

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24 pages, 3362 KiB

Open AccessArticle

P2X7 Receptors and TMEM16 Channels Are Functionally Coupled with Implications for Macropore Formation and Current Facilitation

by Kate Dunning, Adeline Martz, Francisco Andrés Peralta, Federico Cevoli, Eric Boué-Grabot, Vincent Compan, Fanny Gautherat, Patrick Wolf, Thierry Chataigneau and Thomas Grutter

Int. J. Mol. Sci. 2021, 22(12), 6542; https://doi.org/10.3390/ijms22126542 - 18 Jun 2021

Cited by 13 | Viewed by 3471

Abstract

P2X7 receptors (P2X7) are cationic channels involved in many diseases. Following their activation by extracellular ATP, distinct signaling pathways are triggered, which lead to various physiological responses such as the secretion of pro-inflammatory cytokines or the modulation of cell death. P2X7 also exhibit [...] Read more.

P2X7 receptors (P2X7) are cationic channels involved in many diseases. Following their activation by extracellular ATP, distinct signaling pathways are triggered, which lead to various physiological responses such as the secretion of pro-inflammatory cytokines or the modulation of cell death. P2X7 also exhibit unique behaviors, such as “macropore” formation, which corresponds to enhanced large molecule cell membrane permeability and current facilitation, which is caused by prolonged activation. These two phenomena have often been confounded but, thus far, no clear mechanisms have been resolved. Here, by combining different approaches including whole-cell and single-channel recordings, pharmacological and biochemical assays, CRISPR/Cas9 technology and cell imaging, we provide evidence that current facilitation and macropore formation involve functional complexes comprised of P2X7 and TMEM16, a family of Ca²⁺-activated ion channel/scramblases. We found that current facilitation results in an increase of functional complex-embedded P2X7 open probability, a result that is recapitulated by plasma membrane cholesterol depletion. We further show that macropore formation entails two distinct large molecule permeation components, one of which requires functional complexes featuring TMEM16F subtype, the other likely being direct permeation through the P2X7 pore itself. Such functional complexes can be considered to represent a regulatory hub that may orchestrate distinct P2X7 functionalities. Full article

(This article belongs to the Special Issue Purinergic P2 Receptors: Structure and Function 2.0)

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18 pages, 10247 KiB

Open AccessArticle

Confocal Blood Flow Videomicroscopy of Thrombus Formation over Human Arteries and Local Targeting of P2X7

by Patrizia Marchese, Maria Lombardi, Maria Elena Mantione, Domenico Baccellieri, David Ferrara, Roberto Chiesa, Ottavio Alfieri and Chiara Foglieni

Int. J. Mol. Sci. 2021, 22(8), 4066; https://doi.org/10.3390/ijms22084066 - 14 Apr 2021

Cited by 2 | Viewed by 2895

Abstract

Atherothrombosis exposes vascular components to blood. Currently, new antithrombotic therapies are emerging. Herein we investigated thrombogenesis of human arteries with/without atherosclerosis, and the interaction of coagulation and vascular components, we and explored the anti-thrombogenic efficacy of blockade of the P2X purinoceptor 7 (P2X7). [...] Read more.

Atherothrombosis exposes vascular components to blood. Currently, new antithrombotic therapies are emerging. Herein we investigated thrombogenesis of human arteries with/without atherosclerosis, and the interaction of coagulation and vascular components, we and explored the anti-thrombogenic efficacy of blockade of the P2X purinoceptor 7 (P2X7). A confocal blood flow videomicroscopy system was performed on cryosections of internal mammary artery (IMA) or carotid plaque (CPL) determining/localizing platelets and fibrin. Blood from healthy donors elicited thrombi over arterial layers. Confocal microscopy associated thrombus with tissue presence of collagen type I, laminin, fibrin(ogen) and tissue factor (TF). The addition of antibodies blocking TF (aTF) or factor XI (aFXI) to blood significantly reduced fibrin deposition, variable platelet aggregation and aTF + aFXI almost abolished thrombus formation, showing synergy between coagulation pathways. A scarce effect of aTF over sub-endothelial regions, more abundant in tissue TF and bundles of laminin and collagen type I than deep intima, may suggest tissue thrombogenicity as molecular structure-related. Consistently with TF-related vascular function and expression of P2X7, the sections from CPL but not IMA tissue cultures pre-treated with the P2X7 antagonist A740003 demonstrated poor thrombogenesis in flow experiments. These data hint to local targeting studies on P2X7 modulation for atherothrombosis prevention/therapy. Full article

(This article belongs to the Special Issue Purinergic P2 Receptors: Structure and Function 2.0)

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16 pages, 3519 KiB

Open AccessArticle

Characterization of Potency of the P2Y13 Receptor Agonists: A Meta-Analysis

by Chrisanne Dsouza and Svetlana V Komarova

Int. J. Mol. Sci. 2021, 22(7), 3468; https://doi.org/10.3390/ijms22073468 - 27 Mar 2021

Cited by 6 | Viewed by 3119

Abstract

P2Y13 is an ADP-stimulated G-protein coupled receptor implicated in many physiological processes, including neurotransmission, metabolism, pain, and bone homeostasis. Quantitative understanding of P2Y13 activation dynamics is important for translational studies. We systematically identified PubMed annotated studies that characterized concentration-dependence of P2Y13 responses to [...] Read more.

P2Y13 is an ADP-stimulated G-protein coupled receptor implicated in many physiological processes, including neurotransmission, metabolism, pain, and bone homeostasis. Quantitative understanding of P2Y13 activation dynamics is important for translational studies. We systematically identified PubMed annotated studies that characterized concentration-dependence of P2Y13 responses to natural and synthetic agonists. Since the comparison of the efficacy (maximum response) is difficult for studies performed in different systems, we normalized the data and conducted a meta-analysis of EC₅₀ (concentration at half-maximum response) and Hill coefficient (slope) of P2Y13-mediated responses to different agonists. For signaling events induced by heterologously expressed P2Y13, EC₅₀ of ADP-like agonists was 17.2 nM (95% CI: 7.7–38.5), with Hills coefficient of 4.4 (95% CI: 3.3–5.4), while ATP-like agonists had EC₅₀ of 0.45 μM (95% CI: 0.06–3.15). For functional responses of endogenously expressed P2Y13, EC₅₀ of ADP-like agonists was 1.76 μM (95% CI: 0.3–10.06). The EC₅₀ of ADP-like agonists was lower for the brain P2Y13 than the blood P2Y13. ADP-like agonists were also more potent for human P2Y13 compared to rodent P2Y13. Thus, P2Y13 appears to be the most ADP-sensitive receptor characterized to date. The detailed understanding of tissue- and species-related differences in the P2Y13 response to ADP will improve the selectivity and specificity of future pharmacological compounds. Full article

(This article belongs to the Special Issue Purinergic P2 Receptors: Structure and Function 2.0)

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