scholarly journals ATP release through pannexon channels

2015 ◽  
Vol 370 (1672) ◽  
pp. 20140191 ◽  
Author(s):  
Gerhard Dahl
Keyword(s):  
Purinergic Receptors ◽  
Control Mechanism ◽  
Atp Release ◽  
Extracellular Adenosine ◽  
Large Channel ◽  
Selective Channel ◽  
And Control ◽  
Atp Efflux ◽  
Excessive Activation ◽  
Voltage Activation

Extracellular adenosine triphosphate (ATP) serves as a signal for diverse physiological functions, including spread of calcium waves between astrocytes, control of vascular oxygen supply and control of ciliary beat in the airways. ATP can be released from cells by various mechanisms. This review focuses on channel-mediated ATP release and its main enabler, Pannexin1 (Panx1). Six subunits of Panx1 form a plasma membrane channel termed ‘pannexon’. Depending on the mode of stimulation, the pannexon has large conductance (500 pS) and unselective permeability to molecules less than 1.5 kD or is a small (50 pS), chloride-selective channel. Most physiological and pathological stimuli induce the large channel conformation, whereas the small conformation so far has only been observed with exclusive voltage activation of the channel. The interaction between pannexons and ATP is intimate. The pannexon is not only the conduit for ATP, permitting ATP efflux from cells down its concentration gradient, but the pannexon is also modulated by ATP. The channel can be activated by ATP through both ionotropic P2X as well as metabotropic P2Y purinergic receptors. In the absence of a control mechanism, this positive feedback loop would lead to cell death owing to the linkage of purinergic receptors with apoptotic processes. A control mechanism preventing excessive activation of the purinergic receptors is provided by ATP binding (with low affinity) to the Panx1 protein and gating the channel shut.

scholarly journals Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model

2021 ◽  
Vol 22 (13) ◽  
pp. 6910
Author(s):  
Flora Szeri ◽  
Valentina Corradi ◽  
Fatemeh Niaziorimi ◽  
Sylvia Donnelly ◽  
Gwenaëlle Conseil ◽  
...  
Keyword(s):  
Binding Site ◽  
Efflux Pump ◽  
Substrate Binding ◽  
Functional Characterization ◽  
Atp Release ◽  
Homology Model ◽  
Atp Binding ◽  
Atp Binding Site ◽  
Binding Cavity ◽  
Atp Efflux

Inactivating mutations in ABCC6 underlie the rare hereditary mineralization disorder pseudoxanthoma elasticum. ABCC6 is an ATP-binding cassette (ABC) integral membrane protein that mediates the release of ATP from hepatocytes into the bloodstream. The released ATP is extracellularly converted into pyrophosphate, a key mineralization inhibitor. Although ABCC6 is firmly linked to cellular ATP release, the molecular details of ABCC6-mediated ATP release remain elusive. Most of the currently available data support the hypothesis that ABCC6 is an ATP-dependent ATP efflux pump, an un-precedented function for an ABC transporter. This hypothesis implies the presence of an ATP-binding site in the substrate-binding cavity of ABCC6. We performed an extensive mutagenesis study using a new homology model based on recently published structures of its close homolog, bovine Abcc1, to characterize the substrate-binding cavity of ABCC6. Leukotriene C4 (LTC4), is a high-affinity substrate of ABCC1. We mutagenized fourteen amino acid residues in the rat ortholog of ABCC6, rAbcc6, that corresponded to the residues in ABCC1 found in the LTC4 binding cavity. Our functional characterization revealed that most of the amino acids in rAbcc6 corresponding to those found in the LTC4 binding pocket in bovine Abcc1 are not critical for ATP efflux. We conclude that the putative ATP binding site in the substrate-binding cavity of ABCC6/rAbcc6 is distinct from the bovine Abcc1 LTC4-binding site.

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.

P2X7 receptor cross-talk regulates ATP-induced pannexin 1 internalization

2017 ◽  
Vol 474 (13) ◽  
pp. 2133-2144 ◽  
Author(s):  
Andrew K.J. Boyce ◽  
Leigh Anne Swayne
Keyword(s):  
Nervous System ◽  
Cross Talk ◽  
Purinergic Receptors ◽  
Atp Release ◽  
Extracellular Atp ◽  
Signalling Pathways ◽  
Physical Interaction ◽  
Cell Periphery ◽  
Dependent Manner ◽  
Pannexin 1

In the nervous system, extracellular ATP levels transiently increase in physiological and pathophysiological circumstances, effecting key signalling pathways in plasticity and inflammation through purinergic receptors. Pannexin 1 (Panx1) forms ion- and metabolite-permeable channels that mediate ATP release and are particularly enriched in the nervous system. Our recent study demonstrated that elevation of extracellular ATP triggers Panx1 internalization in a concentration- and time-dependent manner. Notably, this effect was sensitive to inhibition of ionotropic P2X7 purinergic receptors (P2X7Rs). Here, we report our novel findings from the detailed investigation of the mechanism underlying P2X7R–Panx1 cross-talk in ATP-stimulated internalization. We demonstrate that extracellular ATP triggers and is required for the clustering of P2X7Rs and Panx1 on Neuro2a cells through an extracellular physical interaction with the Panx1 first extracellular loop (EL1). Importantly, disruption of P2X7R–Panx1 clustering by mutation of tryptophan 74 within the Panx1 EL1 inhibits Panx1 internalization. Notably, P2X7R–Panx1 clustering and internalization are independent of P2X7R-associated intracellular signalling pathways (Ca2+ influx and Src activation). Further analysis revealed that cholesterol is required for ATP-stimulated P2X7R–Panx1 clustering at the cell periphery. Taken together, our data suggest that extracellular ATP induces and is required for Panx1 EL1-mediated, cholesterol-dependent P2X7R–Panx1 clustering and endocytosis. These findings have important implications for understanding the role of Panx1 in the nervous system and provide important new insights into Panx1–P2X7R cross-talk.

Seeking Solutions for Enhancing Social Relations and Communication in Media-Dependent Children of the Digital Age

2019 ◽  
pp. 60-71
Author(s):  
Tuğba Akdal
Keyword(s):  
Information Flow ◽  
Social Relations ◽  
Social Order ◽  
Control Mechanism ◽  
Communicative Action ◽  
Digital Age ◽  
Mental Processes ◽  
Control Power ◽  
Communication Devices ◽  
And Control

The technological age we're in removes all the temporal and spatial boundaries of communication and continues to provide various opportunities and conveniences for us. However, in this digital age in which individuals face intense information flow every day along with these opportunities, the effectiveness and control power of means of communication also increase. In today's capitalist or modern social order, a child model whose mental processes in a consumption-oriented way, who fully gets hold of the control mechanism and acts as an adult is being created. Parent profile of modern order accepts this model and they expect their children to behave as adults. The aim of this study is to find solutions to problems children—who have increasingly become dependent on communication devices of the digital age—face in socializing, establishing realistic relationships, and getting included within the communicative action of a realistic world to guide and raise awareness within parents for developing new communicative methods and skills with the children who have almost become mechanized.

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