Areas of Interest
Role of phospholipids in signal transduction at cell-surface receptors.
Professor of Pharmacology and Senior Research Scientist at the Mental Health Research Institute. Role of phospholipids in signal transduction at cell-surface receptors. Functional roles of phosphoinositides in receptor endocytosis, maintenance of the actin cytoskeleton and in regulation of cell volume.
The focus of this laboratory is that of the role played by phosphoinositides (inositol-containing phospholipids) in the cell biology of neural cells. These quantitatively minor phospholipids, which are prevalent within the nervous system, are known to play an important role in signal transduction events at neural membranes since their turnover is linked to the activation of a pharmacologically distinct group of cell-surface receptors. This then leads to activation of phospholipase C and the subsequent formation of intracellular second messengers involved in calcium homeostasis and protein phosphorylation. It has also become evident that inositol lipids may play important roles in other aspects of the cell biology of neurons. Elucidation of the roles for phosphoinositides in such functions as the internalization (endocytosis) of cell surface receptors and in maintenance of the actin cytoskeleton have been major research objectives of this laboratory. In addition, regulation of the homeostasis of myo-inositol, a key precursor molecule for phosphoinositide synthesis, has been investigated using human NT2-N neurons. The availability of inositol may be of major importance to our understanding of the therapeutic efficacy of lithium salts, which, to date, are the most effective form of treatment for manic-depressive psychosis. Most recently we have observed that receptor-stimulated phosphoinositide hydrolysis may facilitate the regulatory changes in brain cell volume following hypoosmotic stress (encountered during hyponatremia and other clinically relevant conditions). Increases in the volume of brain cells is of major physiological importance because of limitations of the skull. Our results suggest that cell surface receptors, operating via phospholipase C, can increase the release of small organic osmolytes such as inositol, taurine and glutamate. The release of the compounds is part of a regulatory volume decrease mechanism that restores the volume of brain cells.
- Novak JE, Agranoff BW, and Fisher SK: Regulation of myo-inositol homeostasis in differentiated human NT2-N neurons. Neurochem. Res. 25:561-566, 2000.
- Linseman DA, Hofmann F, and Fisher SK: A role for the small molecular weight GTPases, Rho and Cdc42, in muscarinic receptor signaling to focal adhesion kinase. J. Neurochem. 74:2010-2020, 2000.
- Novak JE, Agranoff BW, and Fisher SK: Increased expression of G alpha q/11 and of phospholipase C beta 1/4 in differentiated human NT2-N neurons: enhancement of phosphoinositide hydrolysis. J. Neurochem. 74:2322-2330, 2000.
- Holz RW, Hlubek MD, Sorensen SD, Fisher SK, Balla T, Ozaki S, Prestwich GD, Stuenkel EL, and Bittner MA: A pleckstrin homology domain specific for PtdIns-4-5-P2 and fused to green fluorescent protein identifies plasma membrane PtdIns-4-5-P2 as being important in exocytosis. J. Biol. Chem. 275:17878-17885, 2000.
- Linseman DA, Heidenreich KA, and Fisher SK: Stimulation of M3 muscarinic receptors induces phosphorylation of the cdc42 effector activated cdc42Hs-associated kinase via a fyn tyrosine kinase signaling pathway. J. Biol. Chem. 276:5622-5628, 2001.
- Fisher SK, Novak JE, and Agranoff BW: Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance. J. Neurochem. 82:736-754, 2002.