A growing body of literature suggests that certain ion channels participate in fundamental aspects of a cells' biology that are unrelated to electrical signaling. Hence such channels are particularly relevant to non-excitable cells such as glial cells. In this proposal we are examining the role of Ca2+-activated K* channels (KCa), a super-family of ion channels that have the unique ability to translate changes in intracellular Ca2+ to changes in K+ conductance and resting membrane potential. Ca2+ signaling appears to be particularly important in glial cells where propagating waves of activity can be observed in vitro and in vivo under both physiological conditions and in the context of disease and injury. We suggest that KCa channels are a downstream target of Ca2+ waves but also respond to growth factors and cytokines that trigger Ca2+ signals. We suggest in this proposal that KCa channels are of particular importance in glial cells: Wehypothesize that activation of KCa channels is essential in thecoordinated migration of glial cells during brain development,in malignancy and following injury. In this context, KCa channels participate in dynamic shape changes of the glial """"""""invadipodia"""""""" but also play an important role in regulating programmed cells death (apoptosis). We further hypothesize that the function of KCa channels is most pronounced in glial populations that are still migratory and/or proliferative. Upon differentiation these channels are down regulated and replaced by Kir channels that aid in K+ homeostasis in the brain. However, KCa expression and function can be re-acquired in glial cells following acute injury (gliosis) and in disease states in which glial migration is prominent. The latter includes glial derived tumors that invade diffusely into normal brain.
| Thompson, Emily G; Sontheimer, Harald (2016) A role for ion channels in perivascular glioma invasion. Eur Biophys J 45:635-648 |
| Kimbrough, Ian F; Robel, Stefanie; Roberson, Erik D et al. (2015) Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. Brain 138:3716-33 |
| Robert, Stephanie M; Buckingham, Susan C; Campbell, Susan L et al. (2015) SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med 7:289ra86 |
| Robel, Stefanie; Buckingham, Susan C; Boni, Jessica L et al. (2015) Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci 35:3330-45 |
| Cuddapah, Vishnu Anand; Robel, Stefanie; Watkins, Stacey et al. (2014) A neurocentric perspective on glioma invasion. Nat Rev Neurosci 15:455-65 |
| Turner, Kathryn L; Honasoge, Avinash; Robert, Stephanie M et al. (2014) A proinvasive role for the Ca(2+) -activated K(+) channel KCa3.1 in malignant glioma. Glia 62:971-81 |
| Turner, Kathryn L; Sontheimer, Harald (2014) Cl- and K+ channels and their role in primary brain tumour biology. Philos Trans R Soc Lond B Biol Sci 369:20130095 |
| Robert, Stephanie M; Ogunrinu-Babarinde, Toyin; Holt, Kenneth T et al. (2014) Role of glutamate transporters in redox homeostasis of the brain. Neurochem Int 73:181-91 |
| Turner, Kathryn L; Sontheimer, Harald (2014) KCa3.1 modulates neuroblast migration along the rostral migratory stream (RMS) in vivo. Cereb Cortex 24:2388-400 |
| Watkins, Stacey; Robel, Stefanie; Kimbrough, Ian F et al. (2014) Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat Commun 5:4196 |
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