Stephen K. Fisher, Ph.D.

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.