The arachidonic acid cascade, eicosanoids, and signal transduction.

Janssen-Timmen U, Tomic I, Specht E, Beilecke U, Habenicht AJ.

Department of Medicine, University of Heidelberg, Germany.

Eicosanoid biosynthesis in animal cells either results from agonist-stimulated

phospholipase activation (endogenous pathway) or from lipoprotein receptor-mediated
uptake and lysosomal lipid hydrolase-dependent release of AA (exogenous pathway) (see
Fig. 1 for schematic representation). LDL stimulates eicosanoid formation through
delivery of substrate AA to enzymes of oxidative AA metabolism. The classical LDL
receptor is a control point of the effects of LDL AA on eicosanoid formation in different
tissues: LDL AA metabolism occurs in several cell types of mesenchymal and epithelial
origin and generates the formation of distinct eicosanoid patterns in each case. The LDL
AA pathway does appear to couple directly to the PGH synthase reaction, whereas it does
not couple directly to the 5-lipoxygenase reaction. We expect that a more complete
characterization of the LDL unsaturated fatty acid pathway in different tissue will yield
additional information on the biochemistry of lipoproteins, AA, and eicosanoids.
Selenium deficiency alters the formation of eicosanoids and signal
transduction in rat lymphocytes.

Cao YZ, Weaver JA, Reddy CC, Sordillo LM.

Department of Veterinary Science, Center for Mastitis Research, Pennsylvania State

University, University Park 16802-3500, USA.

Previous reports have shown that selenium (Se) nutrition alters the lipoxygenase pathway
and mitogenic responses in bovine lymphocytes. In order to further understand how Se
may alter lymphocyte function, we examined the effects of Se nutrition on arachidonic
acid (AA) metabolism and phospholipase D (PLD) activation. Lymphocytes were
isolated from the lymph nodes of rats fed either Se-deficient diet (-Se) or Se-
supplemented diet (+Se) for 12 weeks. Our results revealed that calcium ionophore
A23187-stimulated lymphocytes derived from -Se rats produced significantly less
prostaglandins (PGs) than those obtained from +Se rats. Phospholipase D (PLD)
activation by 12-O-tetradecanoylphorbol-13-acetate (TPA) was significantly lower in
lymphocytes obtained from -Se rats when compared to cells from +Se rats. Furthermore,
the addition of PGE2, PGD2 or PGF2alpha to suspended lymphocytes from -Se rats
significantly enhanced PLD activity. The effects of TPA and PGE2 on PLD activation
were additive. However, the addition of PGE2 abolished the significant difference in PLD
activation between -Se and +Se cells observed in response to TPA alone. Based on these
results, we postulate that dietary Se status plays an important role in the regulation of AA
metabolism that subsequently affects PLD activation.
G protein and eicoasanoids:

The overall physiology can be summarized like this: an extracellular

messenger binds to a specific receptor on a cell surface. The receptor
changes conformation, and interacts with a Gp protein. The Gp protein
activates a PLC, which splits PIP2 into DAG and IP3. The IP3 interacts
with Ca++ channels on the membrane of the calcium-sequestering
compartment. Ca++ flows into the cytosolic compartment where it
interacts with calmodulin. The Ca++-calmodulin complex then activates
target proteins.

The story is not quite complete because the PLC step actually activates
two signaling pathways. The DAG formed by hydrolysis of the IP3 may
express two roles in cell signaling. For one, arachidonic acid may be
hydrolyzed from the DAG. The free arachidonic acid is taken into
biosynthesis of prostaglandins and other eicosanoids. As we mentioned
before, eicosanoids can modulate cellular responses to hormones. For
just a bit more detail on eicosanoid actions, most eicosanoids are
thought to act through specific cell surface receptors. The receptors act
through G proteins to modify the cAMP and C-kinase pathways. For an
example, a diuretic hormone known as AVP increases fluid secretion in
mammalian kidneys. At the same time, certain prostaglandins attenuate
the intensity of fluid secretion. Hence, the overall secretory response to
the hormone is the outcome of multiple signal transduction pathways.

Prostaglandin receptors: Prostaglandins and related compounds are transported out

of the cells that synthesize them. Most affect other cells by interacting with plasma
membrane G-protein coupled receptors. Depending on the cell type, the activated G
protein may stimulate or inhibit formation of cAMP, or may activate a
phosphatidylinositol signal pathway leading to intracellular Ca++ release. Another
prostaglandin receptor, designated PPAR, is related to a family of nuclear receptors with
transcription factor activity.
Prostaglandin receptors are specified by the same letter code. For example:
Receptors for E-class prostaglandins are designated EP.
Thromboxane receptors are designated TP.
Multiple receptors for a prostaglandin are specified by subscripts (e.g., EP1, EP2, EP3,
etc.). Different receptors for a particular prostaglandin may activate different signal
cascades. Effects may vary in different tissues, depending on which receptors are
expressed