title: Inhibition of Kv1.3 potassium current by phosphoinositides and stromal-derived factor-1alpha in Jurkat T cells.
abstract: The activation of Kv1.3 potassium channel has obligatory roles in immune responses of T lymphocytes. Stromal cell-derived factor-1alpha (SDF-1alpha) binds to C-X-C chemokine receptor type 4, activates phosphoinositide 3-kinase, and plays essential roles in cell migration of T lymphocytes. In this study, the effects of phosphoinositides and SDF-1alpha on Kv1.3 current activity were examined in the Jurkat T cell line using whole cell patch-clamp techniques. The internal application of 10 microM phosphatidylinositol 4,5-bisphosphate (PIP(2)) or 10 microM phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) significantly reduced Kv1.3 current, but that of 10 microM phosphatidylinositol-4-monophosphate (PIP) did not. The coapplication of 10 microg/ml anti-PIP(3) antibody with PIP(2) from the pipette did not change the reduction of Kv1.3 current by PIP(2), but the coapplication of the antibody with PIP(3) eliminated the reduction. The heat-inactivated anti-PIP(3) antibody had no effect on PIP(3)-induced inhibition. These results suggest that PIP(2) per se can reduce Kv1.3 current as well as PIP(3). External application of 1 muM Akt-kinase inhibitor VIII did not reverse the effect of intracellular PIP(3). External application of 10 and 30 ng/ml SDF-1alpha significantly reduced Kv1.3 current. Internal application of anti-PIP(3) antibody reversed the SDF-1alpha-induced reduction. These results suggest that, in Jurkat T cells, PIP(2), PIP(3), and SDF-1alpha reduce Kv1.3 channel activity and that the reduction by SDF-1alpha may be mediated by the enhancement of PIP(3) production. These novel inhibitory effects of phosphoinositides and SDF-1alpha on Kv1.3 current may have a significant function as a downregulation mechanism of Kv1.3 activity for the maintenance of T lymphocyte activation in immune responses.
authors.affiliation: Dept. of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohya
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Haruna
authors.initials: H
authors.lastname: Itoda
authors.forename: Takuya
authors.initials: T
authors.lastname: Kimura
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Imaizumi
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000378:metabolism* / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000276:immunology*; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism* / Q000494:pharmacology; D018129:Phosphatidylinositol Phosphates / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*
chemical_list: D000906:Antibodies; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D051664:Kv1.3 Potassium Channel; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D051057:Proto-Oncogene Proteins c-akt