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Alternative splicing of the N-terminal cytosolic and transmembrane domains of P2X7 controls gating of the ion channel by ADP-ribosylation

Schwarz, Nicole ; Drouot, Laurent ; Nicke, Annette ; Fliegert, Ralf ; Boyer, Olivier ; Guse, Andreas H ; Haag, Friedrich ; Adriouch, Sahil ; Koch-Nolte, Friedrich Zhang, Zhe

PloS one, 2012-07, Vol.7 (7), p.e41269-e41269 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Alternative splicing of the N-terminal cytosolic and transmembrane domains of P2X7 controls gating of the ion channel by ADP-ribosylation
Autor: Schwarz, Nicole ; Drouot, Laurent ; Nicke, Annette ; Fliegert, Ralf ; Boyer, Olivier ; Guse, Andreas H ; Haag, Friedrich ; Adriouch, Sahil ; Koch-Nolte, Friedrich
Zhang, Zhe
Assuntos: Activation ; Adenosine diphosphate ; Adenosine Diphosphate Ribose - genetics ; Adenosine Diphosphate Ribose - metabolism ; Adenosine Triphosphate - genetics ; Adenosine Triphosphate - metabolism ; ADP-ribosylation ; Alternative splicing ; Alternative Splicing - physiology ; Amino acids ; Animals ; Apoptosis ; Arginine ; ATP ; Binding ; Binding sites ; Biochemistry ; Biology ; Cell surface ; Channel gating ; Enzymes ; Exons ; Gene mutation ; Gene mutations ; Hazards ; HEK293 Cells ; Hostages ; Humans ; Immune system ; Immunology ; Immunoregulation ; Ion Channel Gating - physiology ; Ion channels ; Lymphocytes ; Lymphocytes T ; Macrophages ; Mice ; Mice, Inbred BALB C ; Mutation ; NAD ; NAD - genetics ; NAD - metabolism ; Point mutation ; Post-translational modification ; Post-translational modifications ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Protein Processing, Post-Translational - physiology ; Protein Structure, Tertiary ; Receptors, Purinergic P2X7 - genetics ; Receptors, Purinergic P2X7 - metabolism ; Ribosylation ; Sensitivity ; Signal transduction ; Splicing ; T cells ; T-Lymphocytes, Regulatory - cytology ; T-Lymphocytes, Regulatory - metabolism ; Transmembrane domains ; Zebrafish
É parte de: PloS one, 2012-07, Vol.7 (7), p.e41269-e41269
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Conceived and designed the experiments: NS LD AN RF SA FKN. Performed the experiments: NS LD AN RF SA. Analyzed the data: NS LD AN RF OB AHG FH SA FKN. Contributed reagents/materials/analysis tools: NS LD AN RF OB AHG FH SA FKN. Wrote the paper: NS FKN.
Competing Interests: The Haag and Koch-Nolte labs receive a share of the revenues from commercial sales of the antibodies described here by MediGate GmbH, a subsidiary of the University Medical Center Hamburg-Eppendorf. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
Descrição: P2X7 is a homotrimeric ion channel with two transmembrane domains and a large extracellular ATP-binding domain. It plays a key role in the response of immune cells to danger signals released from cells at sites of inflammation. Gating of murine P2X7 can be induced by the soluble ligand ATP, as well as by NAD(+)-dependent ADP-ribosylation of arginine 125, a posttranslational protein modification catalyzed by the toxin-related ecto-enzymes ART2.1 and ART2.2. R125 is located at the edge of the ligand-binding crevice. Recently, an alternative splice variant of P2X7, designated P2X7(k), was discovered that differs from the previously described variant P2X7(a) in the N-terminal 42 amino acid residues composing the first cytosolic domain and most of the Tm1 domain. Here we compare the two splice variants of murine P2X7 with respect to their sensitivities to gating by ADP-ribosylation in transfected HEK cells. Our results show that the P2X7(k) variant is sensitive to activation by ADP-ribosylation whereas the P2X7(a) variant is insensitive, despite higher cell surface expression levels. Interestingly, a single point mutation (R276K) renders the P2X7(a) variant sensitive to activation by ADP-ribosylation. Residue 276 is located at the interface of neighboring subunits approximately halfway between the ADP-ribosylation site and the transmembrane domains. Moreover, we show that naive and regulatory T cells preferentially express the more sensitive P2X7(k) variant, while macrophages preferentially express the P2X7(a) variant. Our results indicate that differential splicing of alternative exons encoding the N-terminal cytosolic and transmembrane domains of P2X7 control the sensitivity of different immune cells to extracellular NAD(+) and ATP.
Editor: United States: Public Library of Science
Idioma: Inglês

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Alternative splicing of the N-terminal cytosolic and transmembrane domains of P2X7 controls gating of the ion channel by ADP-ribosylation

Schwarz, Nicole ; Drouot, Laurent ; Nicke, Annette ; Fliegert, Ralf ; Boyer, Olivier ; Guse, Andreas H ; Haag, Friedrich ; Adriouch, Sahil ; Koch-Nolte, Friedrich Zhang, Zhe

United States: Public Library of Science

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