sjf1@columbia.edu

SENIOR RESEARCH SCIENTIST IN PHARMACOLOGY

Arachidonic acid metabolism in inflammatory cells and the nervous system; synthesis, biological and pharmacological activities of leukotrienes and PAF; lipid-sensitive ion channels and cardiac arrhythmia

Arachidonic acid is an essential fatty acid that is metabolized to diverse biologically active products. We study the lipoxgenase metabolites of arachidonate known as leukotrienes. The leukotrienes are important regulators of white blood cell function and therefore play a role in the inflammatory process. We previously demonstrated that leukotriene synthesis occurs through a cooperative interaction between white blood cells and the cells that line the inside of blood vessels, the endothelial cells. We have identified what appears to be a novel kinase that regulates one branch of this pathway. In proper balance, these interactions keep white blood cells from initiating an inflammatory reaction but after the appropriate biological signal, they may serve to amplify the response. We are using high-performance liquid chromatography, immunoassay and gas chromatography/mass spectrometry to measure the production of leukotrienes.

Our second area of interest relates to the role of lipids as signaling molecules in excitable cells. We have looked at the role of platelet-activating factor, a phospholipid made by white blood cells, as an initator of arrhythmias in isolated cardiac myocytes. A larger effort has focused on the synthesis and function of lipoxygenase products in the nervous system. As a model system, we are using the marine mollusk, Aplysia californica. Previously we identified 12-lipoxygenase products as second messengers in identified neurons. More recently, we have identified a new pathway initiated by the 8-lipoxygenase in this same tissue. This new pathway appears to be linked to an unusual, G-protein linked, nicotinic acetylcholine receptor. Continuing biochemical and parallel functional studies are in progress.

Selected Publications:

1.  Feinmark SJ and Cannon PJ:  Endothelial cell leukotriene C₄ synthesis results from intercellular transfer of leukotriene A₄ synthesized by polymorphonuclear leukocytes. J. Biol. Chem. 261:16466-16472, 1986. Abstract PDF File

2. Rybina IV, Liu H, Gor Y and Feinmark SJ:  Regulation of leukotriene A₄ hydrolase activity in endothelial cells by phosphorylation. J. Biol. Chem. 272: 31865-31871, 1997. Abstract PDF file

3. Hoffman BH, Feinmark SJ and Guo S-D:  Electrophysiological effects of interactions between activated canine neutrophils and cardiac myocytes.  J. Cardiovasc. Electrophysiol. 8:679-687, 1997. Abstract

4. Tieman, TL, Steel, DJ, Kehoe, J, Schwartz, JH and Feinmark, SJ: A pertussis toxin-sensitive 8-lipoxygenase pathway is activated by a nicotinic acetylcholine receptor in Aplysia neurons, J. Neurophysiol., 85:2150-2158, 2001. Abstract PDF file

5. Barbuti A, Ishii S, Shimizu T, Robinson RB and Feinmark SJ: Block of the background K⁺ channel TASK-1 contributes to arrhythmogenic effects of platelet-activating factor, Am. J. Physiol. Heart Circ. Physiol., 282:H2024-2030, 2002. Abstract PDF file

6. Feinmark SJ, Begum R, Tsvetkov E, Goussakov I, Funk CD, Siegelbaum SA and Bolshakov VY: 12-lipoxygenase metabolites of arachidonic acid mediate metabotropic glutamate receptor-dependent long-term depression at hippocampal CA3-CA1 synapses. J. Neurosci. 23:11427-11435, 2003. Abstract PDF File

7. Besana A, Barbuti A, Tateyama MA, Symes AJ, Robinson RB and Feinmark SJ: Activation of protein kinase C e inhibits the two-pore domain K⁺ channel, TASK-1, inducing repolarization abnormalities in cardiac ventricular myocytes. J. Biol. Chem. 279:33154-33160, 2004. Abstract PDF File

Separation of leukotriene metabolites derived from endothelial cell cultures can be achieved by high-performance liquid chromatography. Products are  identified by ultraviolet spectroscopy.