An ATP-activated channel is involved in mitogenic stimulation of human T lymphocytes.
We investigated the effect of pharmacologic modulation of the ATP receptor on intracellular ion changes and proliferative response of human peripheral blood lymphocytes (PBLs) and purified T lymphocytes. Extracellular ATP (ATPe) triggered in these cells an increase in the cytoplasmic Ca2+ concentration ([Ca2+]i) and plasma membrane depolarization. Whereas both Ca2+ release from intracellular stores and influx across the plasma membrane were detected in the whole PBL population, only Ca2+ influx was observed in T cells. In the presence of near physiologic extracellular Na+ concentrations (125 mmol/L), Ca2+ permeability through the ATPe-gated channel was very low, suggesting a higher selectivity for monovalent over divalent cations. The selective P2Z agonist benzoylbenzoic ATP (BzATP) increased [Ca2+]i in the presence but not the absence of extracellular Ca2+ and also caused plasma membrane depolarization. The covalent blocker oxidized ATP (oATP), an inhibitor of P2X and P2Z receptors, prevented Ca2+ influx and plasma membrane depolarization, but had no effect on Ca2+ release from stores. Stimulation with ATPe alone had no significant effects on PBL 3H-thymidine incorporation. On the contrary, ATPe or BzATP had a synergistic effect on DNA synthesis stimulated by selective T-cell mitogens such as phytohemagglutinin, anti-CD3 monoclonal antibody, or allogenic PBLs (mixed lymphocyte cultures). Treatment with oATP inhibited mitogenic stimulation by these receptor-directed agents but not by the combined application of the Ca2+ ionophore ionomycin and phorbol myristate acetate. Interleukin-2 partially relieved inhibition by oATP. These results suggest that human T lymphocytes express a plasma membrane channel gated by ATPe that is involved in mitogenic stimulation.
Baricordi
O R
OR
Department of Biochemistry and Molecular Biology, University of Ferrara, Italy.
Ferrari
D
D
Melchiorri
L
L
Chiozzi
P
P
Hanau
S
S
Chiari
E
E
Rubini
M
M
Di Virgilio
F
F
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002451:Cell Compartmentation; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D016853:Muromonab-CD3 / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000187:drug effects* / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D015220:Calcium Channels; D016853:Muromonab-CD3; D010835:Phytohemagglutinins; D018048:Receptors, Purinergic P2; D015222:Sodium Channels; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D002118:Calcium