Unregulated levels of K+ and glutamate in the extracellular synaptic space lead to excitotoxicity and neuronal cell death. Buffering of these metabolites by astrocytes is the major controlling mechanism, and alterations in potassium conductance in astrocytes have been associated with many neurological disorders, including epilepsy and impairments due to traumatic brain injury, demonstrating their critical role in modulation of general neuronal excitability and synaptic transmission. Inward rectifying potassium (Kir) channels in astrocyte membranes are believed to be primarily responsible both for maintaining the astrocyte membrane potential and for potassium buffering/siphoning. However, the molecular basis of astrocyte Kir currents, their rectification properties, and the role of rectification in K+ buffering/siphoning remains unclear. Our goal is to assess the contribution of the different potassium channels in astrocyte function during normal and pathological conditions. Our working hypothesis is that Kir 4.1 plays a major role in potassium buffering and glutamate clearance during normal conditions, whereas Kir 6.1 becomes important during ischemia. To address this hypothesis, we propose the following specific aims:
Aim 1 : To examine the biophysical properties of candidate glial cell Kir channels.
Aim 2 : To determine the role of different molecular entities in glial cell Kir channel activity and K+ buffering.
Aim 3 : To test the hypothesis that Kir4.1 is primarily responsible for neuroprotection during glutamate-induced excitotoxicity, whereas Kir6.1 functions to protect neurons during ischemia. The results of these studies will provide insight into potassium channel function in astrocytes under physiological and pathological conditions and may lead to treatments for nervous system dysfunctions. ? ?
|Sala-Rabanal, Monica; Kucheryavykh, Lilia Y; Skatchkov, Serguei N et al. (2010) Molecular mechanisms of EAST/SeSAME syndrome mutations in Kir4.1 (KCNJ10). J Biol Chem 285:36040-8|
|Inyushin, Mikhail; Kucheryavykh, Lilia Y; Kucheryavykh, Yuriy V et al. (2010) Potassium channel activity and glutamate uptake are impaired in astrocytes of seizure-susceptible DBA/2 mice. Epilepsia 51:1707-13|
|Kucheryavykh, Lilia Y; Kucheryavykh, Yuriy V; Inyushin, Mikhail et al. (2009) Ischemia Increases TREK-2 Channel Expression in Astrocytes: Relevance to Glutamate Clearance. Open Neurosci J 3:40-47|
|Kucheryavykh, Yuriy V; Shuba, Yaroslav M; Antonov, Sergei M et al. (2008) Complex rectification of Muller cell Kir currents. Glia 56:775-90|
|Kucheryavykh, Yuri V; Pearson, Wade L; Kurata, Harley T et al. (2007) Polyamine permeation and rectification of Kir4.1 channels. Channels (Austin) 1:172-8|
|Franze, Kristian; Grosche, Jens; Skatchkov, Serguei N et al. (2007) Muller cells are living optical fibers in the vertebrate retina. Proc Natl Acad Sci U S A 104:8287-92|
|Kucheryavykh, Y V; Kucheryavykh, L Y; Nichols, C G et al. (2007) Downregulation of Kir4.1 inward rectifying potassium channel subunits by RNAi impairs potassium transfer and glutamate uptake by cultured cortical astrocytes. Glia 55:274-81|
|Pearson, Wade L; Skatchkov, Serguei N; Eaton, Misty J et al. (2006) C-terminal determinants of Kir4.2 channel expression. J Membr Biol 213:187-93|
|Skatchkov, S N; Eaton, M J; Shuba, Y M et al. (2006) Tandem-pore domain potassium channels are functionally expressed in retinal (Muller) glial cells. Glia 53:266-76|