Iodide efflux, an index of anion permeability, has been monitored in cultured rat brain endothelial cells. Following hypotonicity-induced swelling, large, rapid increases in permeability occur, the extent of these increases depending on the degree of hypotonicity. Such large responses are not observed with rat aortic endothelial cells. Results of anion substitution experiments suggest that iodide efflux is via a chloride channel rather than an exchanger. The efflux increase is blocked by NPPB (100 microM) but not by DIDS or DPC at 100 microM. It is dependent on intracellular ATP but unaffected by removal of external calcium. Increasing internal calcium using A23187 does not produce a change in efflux, but depletion of calcium reduces or eliminates the response to hypotonicity. The response is reduced by pimozide (2-50 microM) that inhibits the actions of calmodulin and by pBPB (10 microM) that affects phospholipase A2 activity. It is eliminated by 5-lipoxygenase inhibitors (L-656,224 and ETH615, 10 microM) but is unaffected by cyclo-oxygenase inhibitors (indomethacin and piroxicam, 1-100 microM). It is blocked by some modulators of P-glycoprotein activity, e.g., verapamil (100 microM), tamoxifen (50 microM), and progesterone (100 microM) but not by others, e,g., forskolin (40 microM), dideoxyforskolin (40 microM), quinidine (100 microM) and cyclosporin A (10 microM).

01 Jun 1996·Biochemical JournalQ3 · BIOLOGY

Arachidonic acid and lipoxygenase products stimulate protein kinase Cβ mRNA levels in pituitary α T3-1 cell line: role in gonadotropin-releasing hormone action

Q3 · BIOLOGY

Article

Author: BEN-MENAHEM, David ; NAOR, Zvi ; SHRAGA-LEVINE, Zurit

The cross-talk of arachidonic acid (AA) and its lipoxygenase products with protein kinase Cβ (PKCβ) mRNA levels during the action of gonadotropin-releasing hormone (GnRH) was investigated in the pituitary αT3-1 cell line. The addition of AA or its 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid (5-HETE) or leukotriene C4 (LTC4) for 30 or 60 min stimulated PCKβ, but not PKCα mRNA levels (3–5-fold); PCKγ is not expressed by the cells. Other HETEs or leukotrienes tested showed no significant effect. The range of effective concentration for LTC4 and 5-HETE (around 10-10 M) is the range found in GnRH-stimulated pituitary cells. Although PKCβ mRNA levels were preferentially elevated by LTC4 and 5-HETE at early time points, PKCα mRNA levels were elevated at 6–12 h of incubation when PKCβ mRNA levels returned to basal levels. The addition of the phospholipase A2 inhibitor 4-bromophenacyl bromide or the selective 5-lipoxygenase inhibitor L-656,224 abolished [D-Trp6]GnRH (GnRH-A) elevation of PKCβ mRNA levels, whereas PKCα mRNA levels were not increased by this neurohormone. The cyclo-oxygenase inhibitor indomethacin elevated basal PKCβ mRNA levels and potentiated the GnRH-A response. Cross-talk exists between AA and some of its lipoxygenase products and PKCβ gene expression during cell signalling. AA, 5-HETE and LTC4 participate in the rapid stimulation of PKCβ mRNA levels by GnRH.

01 Jan 1994·BiochemistryQ3 · BIOLOGY

Arachidonic acid and Lipoxygenase Products Stimulate Gonadotropin .alpha.-Subunit mRNA Levels in Pituitary .alpha.T3-1 Cell Line: Role in Gonadotropin Releasing Hormone Action

Q3 · BIOLOGY

Article

Author: Ben-Menahem, David ; Limor, Rona ; Shraga-Levine, Zurit ; Naor, Zvi

The role of arachidonic acid (AA) and its lipoxygenase metabolites in gonadotropin releasing hormone (GnRH) induced alpha-subunit gene expression was investigated in the transformed gonadotroph cell line alpha T3-1. The stable analog [D-Trp6]GnRH (GnRHa) stimulated [3H]AA release from prelabeled cells after a lag of 1-2 min. Addition of AA stimulated alpha-subunit mRNA levels in a dose-dependent manner, a significant effect being detected at 5 microM AA. Among various lipoxygenase metabolites of AA, only the 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene C4 (LTC4) stimulated alpha-subunit mRNA levels. However, while 5-HETE and LTC4 (0.1 nM each) were active already after 30 min of incubation, similar to GnRHa, AA (20 microM) stimulated alpha-mRNA levels after 1 h of incubation. Addition of the phospholipase A2 inhibitor 4-bromophenacyl bromide (BPB) or the selective 5-lipoxygenase inhibitor L-656,224 inhibited GnRHa elevation of alpha-subunit mRNA by 65%, while the cyclooxygenase inhibitor indomethacin had no effect. Addition of AA (20 microM) or LTC4 (0.1 nM) to normal cultured rat pituitary cells mimicked the rapid (30 min) stimulatory effect of GnRH (1 nM) upon alpha-subunit, LH beta, and FSH beta mRNA levels, while 5-HETE (0.1 nM) stimulated only FSH beta mRNA levels at this time point. Thus AA and selected 5-lipoxygenase products, in particular LTC4, participate in GnRHa-induced alpha-subunit mRNA elevation.

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