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      Revisiting multimodal activation and channel properties of Pannexin 1

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          Abstract

          Chiu and colleagues review the primary evidence for divergent activation mechanisms and unitary properties of Pannexin 1 channels.

          Abstract

          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.

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          Most cited references86

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          Pannexins, a family of gap junction proteins expressed in brain.

          Database search has led to the identification of a family of proteins, the pannexins, which share some structural features with the gap junction forming proteins of invertebrates and vertebrates. The function of these proteins has remained unclear so far. To test the possibility that pannexins underlie electrical communication in the brain, we have investigated their tissue distribution and functional properties. Here, we show that two of these genes, pannexin 1 (Px1) and Px2, are abundantly expressed in the CNS. In many neuronal cell populations, including hippocampus, olfactory bulb, cortex and cerebellum, there is coexpression of both pannexins, whereas in other brain regions, e.g., white matter, only Px1-positive cells were found. On expression in Xenopus oocytes, Px1, but not Px2 forms functional hemichannels. Coinjection of both pannexin RNAs results in hemichannels with functional properties that are different from those formed by Px1 only. In paired oocytes, Px1, alone and in combination with Px2, induces the formation of intercellular channels. The functional characteristics of homomeric Px1 versus heteromeric Px1/Px2 channels and the different expression patterns of Px1 and Px2 in the brain indicate that pannexins form cell type-specific gap junctions with distinct properties that may subserve different functions.
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            SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel.

            Maintenance of a constant cell volume in response to extracellular or intracellular osmotic changes is critical for cellular homeostasis. Activation of a ubiquitous volume-regulated anion channel (VRAC) plays a key role in this process; however, its molecular identity in vertebrates remains unknown. Here, we used a cell-based fluorescence assay and performed a genome-wide RNAi screen to find components of VRAC. We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. Furthermore, point mutations in SWELL1 cause a significant change in VRAC anion selectivity, demonstrating that SWELL1 is an essential VRAC component. These findings enable further molecular characterization of the VRAC channel complex and genetic studies for understanding the function of VRAC in normal physiology and disease. Copyright © 2014 Elsevier Inc. All rights reserved.
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              Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium.

              The ability for long-range communication through intercellular calcium waves is inherent to cells of many tissues. A dual propagation mode for these waves includes passage of IP3 through gap junctions as well as an extracellular pathway involving ATP. The wave can be regenerative and include ATP-induced ATP release via an unknown mechanism. Here, we show that pannexin 1 channels can be activated by extracellular ATP acting through purinergic receptors of the P2Y group as well as by cytoplasmic calcium. Based on its properties, including ATP permeability, pannexin 1 may be involved in both initiation and propagation of calcium waves.
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                Author and article information

                Journal
                J Gen Physiol
                J. Gen. Physiol
                jgp
                jgp
                The Journal of General Physiology
                The Rockefeller University Press
                0022-1295
                1540-7748
                02 January 2018
                : 150
                : 1
                : 19-39
                Affiliations
                [1]Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA
                Author notes
                Correspondence to Yu-Hsin Chiu: yc6p@ 123456virginia.edu
                Author information
                http://orcid.org/0000-0002-4730-8104
                http://orcid.org/0000-0002-5630-2572
                Article
                201711888
                10.1085/jgp.201711888
                5749114
                29233884
                b5d6cf6d-c1a9-4f4d-bc23-389dd8f6e94a
                © 2018 Chiu et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 27 August 2017
                : 09 November 2017
                Funding
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Award ID: R01 GM107848
                Award ID: P01 HL120840
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                Reviews
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                Anatomy & Physiology
                Anatomy & Physiology

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