Current Research Interests:
A major emphasis of this laboratory is that of the signaling mechanisms that underlie regulatory change in brain cell volume. The CNS is particularly vulnerable to reductions in plasma osmolarity, such as occur during hyponatremia, the most commonly encountered electrolyte disorder in clinical practice. Brain cell swelling is frequently encountered in hyponatremia, a clinical condition that 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. In response to a lowered plasma osmolarity, neural cells initially swell but then are able to restore their volume through the release of osmolytes, both inorganic (K+, Cl-) and organic (taurine, myo-inositol and glutamate) and the exit of osmotically obligated water. Given the importance of the maintenance of cell volume within the CNS, mechanisms underlying the release of osmolytes assume major significance. Our studies indicate that activation of several G-protein–coupled receptors (GPCRs) can dramatically enhance the ability of cells to release osmolytes even under minimal changes in osmolarity (5%)- conditions that are likely to pertain to the in vivo situation. Identification of the signaling pathways involved in the receptor-mediated facilitation of osmolyte release is a major goal and in this context, the availability of calcium and protein kinase C activity appear to be pre-requisites for the optimal release of osmolytes. Furthermore, we have recently demonstrated that the activation of GPCRs may also regulate the re-uptake of osmolytes into neural cells. Approximately 300 GPCRs have been identified in the CNS. The observation that a diverse array of GPCRs can facilitate volume-dependent osmolyte release points to a significant role for this group of receptors in the brain, a tissue particularly vulnerable to osmotic disturbances.
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.
Cheema, T.A., Ward, C.E. and Fisher, S. K., Subnanomolar concentrations of thrombin enhance the volume-sensitive efflux of taurine from human 1321N1 astrocytoma cells, J. Pharmacol. Exp. Ther. 315: 755-763, 2005.
Heacock, A.M., Dodd, M.S. and Fisher, S.K., Regulation of volume-sensitive osmolyte efflux from human SH-SY5Y neuroblastoma cells following activation of lysophospholipid receptors, J. Pharmacol. Exp. Ther. 317: 685-693, 2006.
Heacock, A.M., Foster D.J., and Fisher S.K., Prostanoid receptors regulate the volume-sensitive efflux of osmolytes from murine fibroblasts via a cyclic AMP-dependent mechanism, J. Pharmacol. Exp. Ther. 319: 963-971, 2006.
Cheema, T.A., Pettigrew, V.A. and Fisher, S.K., Receptor regulation of the volume-sensitive efflux of taurine from human SH-SY5Y neuroblastoma cells: Differential requirements for Ca2+ and protein kinase C, J. Pharmacol. Exp. Ther. 320: 1068-1077, 2007.
Cheema, T.A. and Fisher, S.K., Cholesterol regulates volume-sensitive osmolyte efflux from human SH-SY5Y neuroblastoma cells following receptor activation, J. Pharmacol. Exp. Ther. 324: 648-657, 2008.
Foster, D.J., Heacock, A.M., Keep R.F. and Fisher, S.K., Activation of muscarinic cholinergic receptors on human SH-SY5Y neuroblastoma cells enhances both the influx and efflux of K+ under conditions of hypo-osmolarity, J. Pharmacol. Exp. Ther. 325: 457-465, 2008.