Stephen K. Fisher, Ph.D.
Research Professor, MBNI
Professor, Department of Pharmacology

MBNI Labs at Medical Science Research Building II C560A
1150 W. Medical Center Drive
Ann Arbor, MI 48109-0669

skfisher@umich.edu

734-763-4376

Current Research Interests:

One 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, via the phosphodiesteratic breakdown of phosphatidylinositol 4,5-bisphosphate (PIP 2), 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 the latter context, PIP 2 has been shown to play a key role in the tyrosine phosphorylation of focal adhesion kinase, a protein tyrosine kinase that is enriched in neuronal growth cones and plays a role in their remodeling. 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.

A second emphasis is that of the signaling mechanisms that underlie regulatory change in brain cell volume. Brain cell swelling is frequently encountered in hyponatremia, a clinical condition which affects, in particular, the young and the elderly. However, hyponatremia can also impact athletes and the military during times in which there is an over-zealous intake of water or, alternatively, during polydypsia, associated with schizophrenia. One of the mechanisms whereby brain cells restore their volume is via the release of organic osmolytes such as taurine, myo-inositol and glutamate. Our studies indicate that receptor activation can dramatically enhance the ability of cells to release osmolytes even under minimal changes in osmolarity (2-5%)- conditions that are likely to pertain to the invivo situation. To date we have identified at least two pharmacologically distinct receptors (muscarinic cholinergic and thrombin) that facilitate osmolyte release and identification of the signaling pathways involved is a major goal. Elucidation of these pathways will not only contribute to an understanding of the basic mechanisms of cell volume regulation, but also raise the possibility of future therapeutic applications.

Muscarinic receptor remodeling of the actin cytoskeleton in SH-SY5Y neuroblastoma

Phase contrast photomicrograph of human NT2-N ganglia

Selected Publications:

Novak, J.E., Agranoff, B.W. and Fisher, S.K., Increased expression of G a q/ll and of phospholipase C b 1/4 in differentiated human NT2-N neurons: enhancement of phosphoinositide hydrolysis, J. Neurochem. 74:2322-2330, 2000.

Linseman, D.A., Heidenreich, K.A., and Fisher, S.K., 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, S.K., Novak, J.E., Agranoff, B.W., Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance., J Neurochem, 82:736-754, 2002.

Loveday, D., Heacock A.M., Fisher, S.K., Activation of muscarinic cholinergic receptors enhances the volume-sensitive efflux of myo-inositol from SH-SY5Y neuroblastoma cells. J. Neurochem. 87,476-486, 2003.

Heacock, A.M., Kerley, D., Gurda, G.T., VanTroostenberghe, A.T. and Fisher, S.K., Potentiation of the osmosensitive release of taurine and D-Aspartate from SH-SY5Y neuroblastoma cells after activation of M 3 muscarinic cholinergic receptors., J. Pharmacol. Exp. Ther. 311,1097-1104, 2004.