scholarly journals Cryo-EM structures of the ATP release channel pannexin 1

2020 ◽  
Author(s):  
Zengqin Deng ◽  
Zhihui He ◽  
Grigory Maksaev ◽  
Ryan M. Bitter ◽  
Michael Rau ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Homo Sapiens ◽  
Apoptotic Cell ◽  
Purinergic Signaling ◽  
Functional Characterization ◽  
Atp Release ◽  
Release Channel ◽  
Pannexin 1 ◽  
Cell Clearance ◽  
Outer Pore

AbstractThe plasma membrane ATP release channel pannexin 1 has been implicated in numerous physiological and pathophysiological processes associated with purinergic signaling, including cancer progression, apoptotic cell clearance, inflammation, blood pressure regulation, oocyte development, epilepsy and neuropathic pain. Here, we present near-atomic resolution structures of Xenopus tropicalis and Homo sapiens PANX1 determined by cryo-electron microscopy that reveal a heptameric channel architecture. Compatible with ATP permeation, the transmembrane pore and cytoplasmic vestibule are exceptionally wide. An extracellular tryptophan ring located at the outer pore creates a constriction site, potentially functioning as a molecular sieve that restricts the size of permeable substrates. In combination with functional characterization, this work elucidates the previously unknown architecture of pannexin channels and establishes a foundation for understanding their unique channel properties as well as for developing rational therapies.

scholarly journals Revisiting multimodal activation and channel properties of Pannexin 1

2017 ◽  
Vol 150 (1) ◽  
pp. 19-39 ◽  
Author(s):  
Yu-Hsin Chiu ◽  
Michael S. Schappe ◽  
Bimal N. Desai ◽  
Douglas A. Bayliss
Keyword(s):  
Apoptotic Cell ◽  
Purinergic Signaling ◽  
The Body ◽  
Pressure Regulation ◽  
Pannexin 1 ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Channel Expression ◽  
Activation Mechanisms ◽  
Channel Properties

Pannexin 1 (Panx1) forms plasma membrane ion channels that are widely expressed throughout the body. Panx1 activation results in the release of nucleotides such as adenosine triphosphate and uridine triphosphate. Thus, these channels have been implicated in diverse physiological and pathological functions associated with purinergic signaling, such as apoptotic cell clearance, blood pressure regulation, neuropathic pain, and excitotoxicity. In light of this, substantial attention has been directed to understanding the mechanisms that regulate Panx1 channel expression and activation. Here we review accumulated evidence for the various activation mechanisms described for Panx1 channels and, where possible, the unitary channel properties associated with those forms of activation. We also emphasize current limitations in studying Panx1 channel function and propose potential directions to clarify the exciting and expanding roles of Panx1 channels.

scholarly journals Pannexin-1 Deficient Mice Have an Increased Susceptibility for Atrial Fibrillation and Show a QT-Prolongation Phenotype

2016 ◽  
Vol 38 (2) ◽  
pp. 487-501 ◽  
Author(s):  
Stella Petric ◽  
Sofia Klein ◽  
Lisa Dannenberg ◽  
Tillman Lahres ◽  
Lukas Clasen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cardiac Electrophysiology ◽  
Electrophysiological Study ◽  
Atp Release ◽  
Release Channel ◽  
Knock Out ◽  
Pannexin 1 ◽  
Significant Prolongation ◽  
Knock Out Mice

Background/Aims: Pannexin-1 (Panx1) is an ATP release channel that is ubiquitously expressed and coupled to several ligand-gated receptors. In isolated cardiac myocytes, Panx1 forms large conductance channels that can be activated by Ca2+ release from the sarcoplasmic reticulum. Here we characterized the electrophysiological function of these channels in the heart in vivo, taking recourse to mice with Panx1 ablation. Methods: Cardiac phenotyping of Panx1 knock-out mice (Panx1-/-) was performed by employing a molecular, cellular and functional approach, including echocardiography, surface and telemetric ECG recordings with QT analysis, physical stress testing and quantification of heart rate variability. In addition, an in vivo electrophysiological study entailed programmed electrical stimulation using an intracardiac octapolar catheter. Results: Panx1 deficiency results in a higher incidence of AV-block, delayed ventricular depolarisation, significant prolongation of QT- and rate corrected QT-interval and a higher incidence of atrial fibrillation after intraatrial burst stimulation. Conclusion: Panx1 seems to play an important role in murine cardiac electrophysiology and warrants further consideration in the context of hereditary forms of atrial fibrillation.

scholarly journals ATP triggers macropinocytosis that internalizes and is regulated by PANX1

2020 ◽  
Author(s):  
Andrew K.J. Boyce ◽  
Emma van der Slagt ◽  
Juan C. Sanchez-Arias ◽  
Leigh Anne Swayne
Keyword(s):  
Neuroblastoma Cells ◽  
Atp Release ◽  
Surface Proteins ◽  
Cell Area ◽  
Release Channel ◽  
Cross Sectional ◽  
Pannexin 1 ◽  
Disease States ◽  
Cellular Area ◽  
Area Expansion

ABSTRACTMacropinocytosis is an endocytic process that allows cells to respond to changes in their environment by internalizing nutrients and cell surface proteins, as well as modulating cell size. Here, we identify that adenosine triphosphate (ATP) triggers macropinocytosis in murine neuroblastoma cells, thereby internalizing the ATP release channel pannexin 1 (PANX1) while concurrently increasing cross-sectional cellular area. Amiloride, a potent inhibitor of macropinocytosis-associated GTPases, abolished ATP-induced PANX1 internalization and cell area expansion. Transient expression of the GTP-hydrolysis resistant GTPase ARF6 Q67L led to increased PANX1 internalization and increased cell area equivalent to levels seen with ATP stimulation. Mutation of an extracellular tryptophan (W74) in PANX1 abolished ATP-evoked cell area enlargement suggesting that PANX1 regulates this form of macropinocytosis. This novel role of PANX1 in macropinocytosis could be particularly important for disease states implicating PANX1, such as cancer, where ATP can act as a purinergic regulator of cell growth/metastasis and as a supplementary energy source following internalization.

scholarly journals Structure versus function: Are new conformations of pannexin 1 yet to be resolved?

2021 ◽  
Vol 153 (5) ◽  
Author(s):  
Carsten Mim ◽  
Guy Perkins ◽  
Gerhard Dahl
Keyword(s):  
Structural Information ◽  
Purinergic Signaling ◽  
Atp Release ◽  
Strong Support ◽  
Decisive Role ◽  
Chloride Ions ◽  
Pannexin 1 ◽  
Selective Membrane ◽  
Selective Channel ◽  
Structure Versus

Pannexin 1 (Panx1) plays a decisive role in multiple physiological and pathological settings, including oxygen delivery to tissues, mucociliary clearance in airways, sepsis, neuropathic pain, and epilepsy. It is widely accepted that Panx1 exerts its role in the context of purinergic signaling by providing a transmembrane pathway for ATP. However, under certain conditions, Panx1 can also act as a highly selective membrane channel for chloride ions without ATP permeability. A recent flurry of publications has provided structural information about the Panx1 channel. However, while these structures are consistent with a chloride selective channel, none show a conformation with strong support for the ATP release function of Panx1. In this Viewpoint, we critically assess the existing evidence for the function and structure of the Panx1 channel and conclude that the structure corresponding to the ATP permeation pathway is yet to be determined. We also list a set of additional topics needing attention and propose ways to attain the large-pore, ATP-permeable conformation of the Panx1 channel.

scholarly journals Pannexin-1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration

2018 ◽  
Author(s):  
Marco Tozzi ◽  
Jacob B. Hansen ◽  
Ivana Novak
Keyword(s):  
Adipose Tissue ◽  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Cell Metabolism ◽  
Atp Release ◽  
Extracellular Atp ◽  
Adrenergic Stimulation ◽  
Pannexin 1 ◽  
White Adipocytes ◽  
Obesity And Diabetes

One-sentence summaryInsulin inhibits ATP release in adipocytesAbstractExtracellular ATP signaling is involved in many physiological and pathophysiological processes, and purinergic receptors are targets for drug therapy in several diseases, including obesity and diabetes. Adipose tissue has crucial functions in lipid and glucose metabolism and adipocytes express purinergic receptors. However, the sources of extracellular ATP in adipose tissue are not yet characterized.Here, we show that upon adrenergic stimulation white adipocytes release ATP through the pannexin-1 pore that is regulated by a cAMP-PKA dependent pathway. The ATP release correlates with increased cell metabolism, and extracellular ATP induces Ca2+ signaling and lipolysis in adipocytes and promotes macrophages migration. Most importantly, ATP release is markedly inhibited by insulin, and thereby auto/paracrine purinergic signaling in adipose tissue would be attenuated. Furthermore, we define the signaling pathway for insulin regulated ATP release.Our findings reveal the insulin-pannexin-1-purinergic signaling cross-talk in adipose tissue and we propose that deregulation of this signaling may underlie adipose tissue inflammation and type-2 diabetes.

scholarly journals HIV gp120 Protein Increases the Function of Connexin 43 Hemichannels and Pannexin-1 Channels in Astrocytes: Repercussions on Astroglial Function

2020 ◽  
Vol 21 (7) ◽  
pp. 2503 ◽  
Author(s):  
Rosario Gajardo-Gómez ◽  
Cristian A. Santibañez ◽  
Valeria C. Labra ◽  
Gonzalo I. Gómez ◽  
Eliseo A. Eugenin ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Purinergic Signaling ◽  
Atp Release ◽  
P38 Map Kinase ◽  
Motor Deficits ◽  
Pannexin 1 ◽  
Channel Opening ◽  
Wide Range

At least half of human immunodeficiency virus (HIV)-infected individuals suffer from a wide range of cognitive, behavioral and motor deficits, collectively known as HIV-associated neurocognitive disorders (HAND). The molecular mechanisms that amplify damage within the brain of HIV-infected individuals are unknown. Recently, we described that HIV augments the opening of connexin-43 (Cx43) hemichannels in cultured human astrocytes, which result in the collapse of neuronal processes. Whether HIV soluble viral proteins such as gp120, can regulate hemichannel opening in astrocytes is still ignored. These channels communicate the cytosol with the extracellular space during pathological conditions. We found that gp120 enhances the function of both Cx43 hemichannels and pannexin-1 channels in mouse cortical astrocytes. These effects depended on the activation of IL-1β/TNF-α, p38 MAP kinase, iNOS, cytoplasmic Ca2+ and purinergic signaling. The gp120-induced channel opening resulted in alterations in Ca2+ dynamics, nitric oxide production and ATP release. Although the channel opening evoked by gp120 in astrocytes was reproduced in ex vivo brain preparations, these responses were heterogeneous depending on the CA1 region analyzed. We speculate that soluble gp120-induced activation of astroglial Cx43 hemichannels and pannexin-1 channels could be crucial for the pathogenesis of HAND.

scholarly journals Role of an Aromatic–Aromatic Interaction in the Assembly and Trafficking of the Zebrafish Panx1a Membrane Channel

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 272 ◽  
Author(s):  
Ksenia Timonina ◽  
Anna Kotova ◽  
Georg Zoidl
Keyword(s):  
Atp Release ◽  
Integral Membrane Protein ◽  
Membrane Channel ◽  
Release Channel ◽  
Post Translational Modifications ◽  
Mutant Proteins ◽  
Pannexin 1 ◽  
Interaction Testing ◽  
Insight Into

Pannexin 1 (Panx1) is a ubiquitously expressed hexameric integral membrane protein known to function as an adenosine triphosphate (ATP) release channel. Panx1 proteins exist in unglycosylated core form (Gly0). They undergo critical post-translational modifications forming the high mannose glycosylation state (Gly1) in the endoplasmic reticulum (ER) and the complex glycosylation state (Gly2) in the Golgi apparatus. The regulation of transition from the ER to the cell membrane is not fully understood. Using site-specific mutagenesis, dye uptake assays, and interaction testing, we identified two conserved aromatic residues, Trp123 and Tyr205, in the transmembrane domains 2 and 3 of the zebrafish panx1a protein. Results suggest that both residues primarily govern the assembly of panx1a subunits into channels, with mutant proteins failing to interact. The results provide insight into a mechanism enabling regulation of Panx1 oligomerization, glycosylation, and trafficking.

scholarly journals Cryo-EM structures of the ATP release channel pannexin 1

2020 ◽  
Vol 27 (4) ◽  
pp. 373-381 ◽  
Author(s):  
Zengqin Deng ◽  
Zhihui He ◽  
Grigory Maksaev ◽  
Ryan M. Bitter ◽  
Michael Rau ◽  
...  
Keyword(s):  
Atp Release ◽  
Release Channel ◽  
Pannexin 1
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