Abstract
Phosphatidylserine (PS) exposure is normally associated with apoptosis and the removal of dying cells. We observed that PS is exposed constitutively at high levels on T lymphocytes that express low levels of the transmembrane tyrosine phosphatase CD45RB. CD45 was shown to be a negative regulator of PS translocation in response to various signals, including activation of the ATP receptor P2X(7). Changes in PS distribution were shown to modulate several membrane activities: Ca(2+) and Na(+) uptake through the P2X(7) cation channel itself; P2X(7)-stimulated shedding of the homing receptor CD62L; and reversal of activity of the multidrug transporter P-glycoprotein. The data identify a role for PS distribution changes in signal transduction, rapidly modulating the activities of several membrane proteins. This seems to be an all-or-none effect, coordinating the activity of most or all the molecules of a target protein in each cell. The data also suggest a new approach to circumventing multidrug resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
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Adenosine Triphosphate / analogs & derivatives
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Adenosine Triphosphate / pharmacology
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Animals
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Annexin A5 / metabolism
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Apoptosis / physiology
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Biological Transport / drug effects
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / physiology
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Calcium / metabolism
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Cell Membrane / drug effects
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Cell Membrane / metabolism*
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Cell Movement / drug effects
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Cell Movement / physiology
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Cell Survival / physiology
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Drug Resistance, Multiple / drug effects
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Ion Channels / drug effects
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Ion Channels / metabolism
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Ion Channels / physiology
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L-Selectin / metabolism
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Leukocyte Common Antigens / genetics
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Leukocyte Common Antigens / metabolism
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Leukocyte Common Antigens / physiology*
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Lymphocytes / drug effects
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Lymphocytes / metabolism*
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Membrane Proteins / metabolism
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Membrane Proteins / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Inbred CBA
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Mice, Knockout
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Mice, Transgenic
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Models, Biological
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Paclitaxel / pharmacokinetics
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Phosphatidylserines / metabolism*
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Purinergic P2 Receptor Agonists
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Receptors, Purinergic P2 / genetics
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Receptors, Purinergic P2 / physiology*
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Receptors, Purinergic P2X7
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Signal Transduction / physiology*
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / physiology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Annexin A5
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Ion Channels
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Membrane Proteins
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P2rx7 protein, mouse
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Phosphatidylserines
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Purinergic P2 Receptor Agonists
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Receptors, Purinergic P2
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Receptors, Purinergic P2X7
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L-Selectin
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3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
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Adenosine Triphosphate
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Leukocyte Common Antigens
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Paclitaxel
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Calcium