Emerging evidence suggests that gap junction hemichannels (HCs) can act as stand alone channels in astrocytes. The actions of gap junctions and HCs are fundamentally different and the Biology of astrocyte HCs is poorly understood. Unlike gap junctions, which connect the interiors of two cells, open HCs directly connect intracellular and extracellular spaces. The proposed experiments will explore the properties of these channels in astrocytes and begin the process of critically testing how they participate in both normal as well as pathological events in the brain. The following hypotheses will be tested: 1) Astrocytes express functional HCs. 2) HCs are gated and/or modulated by multiple factors including divalent cations, pH, membrane potential, glutamate receptor stimulation, prior HC activity and environment. 3) HCs influence transmembrane gradients of glutamate, ions and other small molecules. HCs open during intense neural activity and may participate in normal brain functions. 4) HCs are activated during ischemia and contribute to the pathophysiology of this condition. These experiments will use primary cultured astrocytes, brain slices and an advantageous CMS white matter preparation, the acutely isolated mouse optic nerve. Tissue will be obtained from wild type and from genetically altered mice that do not express specific proteins that form HCs in astrocytes. The behavior of astrocyte HCs will be studied using ion imaging, dye uptake, HPLC amino acid measurements and immunocytochemistry. The proposed studies will provide useful new information about astrocyte HCs, a neglected channel with unique characteristics. These results will have implications for both normal as well as pathological brain function. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS015589-25A2
Application #
7266677
Study Section
Special Emphasis Panel (ZRG1-MDCN-E (91))
Program Officer
Jacobs, Tom P
Project Start
1987-09-01
Project End
2012-02-28
Budget Start
2007-03-01
Budget End
2008-02-28
Support Year
25
Fiscal Year
2007
Total Cost
$374,098
Indirect Cost
Name
University of Washington
Department
Neurology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yang, Xin; Hamner, Margaret A; Brown, Angus M et al. (2014) Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage. Ann Neurol 75:492-507
Brown, Angus M; Evans, Richard D; Black, Joel et al. (2012) Schwann cell glycogen selectively supports myelinated axon function. Ann Neurol 72:406-18
Hamner, Margaret A; Moller, Thomas; Ransom, Bruce R (2011) Anaerobic function of CNS white matter declines with age. J Cereb Blood Flow Metab 31:996-1002
Ye, Zu-Cheng; Oberheim, Nancyann; Kettenmann, Helmut et al. (2009) Pharmacological ""cross-inhibition"" of connexin hemichannels and swelling activated anion channels. Glia 57:258-69
Oberheim, Nancy Ann; Takano, Takahiro; Han, Xiaoning et al. (2009) Uniquely hominid features of adult human astrocytes. J Neurosci 29:3276-87
Ransom, Bruce R; Baltan, Selva B (2009) Axons get excited to death. Ann Neurol 65:120-1
Baltan, Selva; Besancon, Elaine F; Mbow, Brianna et al. (2008) White matter vulnerability to ischemic injury increases with age because of enhanced excitotoxicity. J Neurosci 28:1479-89
Brown, Angus M (2004) Brain glycogen re-awakened. J Neurochem 89:537-52
Brown, Angus M; Baltan Tekkok, Selva; Ransom, Bruce R (2004) Energy transfer from astrocytes to axons: the role of CNS glycogen. Neurochem Int 45:529-36
Ye, Zu-Cheng; Wyeth, Megan S; Baltan-Tekkok, Selva et al. (2003) Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci 23:3588-96

Showing the most recent 10 out of 52 publications