Poster abstracts

Poster number 88 submitted by Cameron Ford

Acid Sensing Ion Channels and Mitochondrial Function

Cameron Ford (Neuroscience Graduate Program), Candice Askwith (Neuroscience Graduate Program)

Abstract:
The acid-sensing ion channels (ASICs) contribute to normal brain function including synaptic plasticity, fear conditioning, learning, and memory. ASICs also contribute to neuronal death in pathologic conditions that cause reductions in extracellular pH and increased oxidative stress (e.g., ischemic brain injury). Interventions involving ASIC inhibition have shown to limit ischemia mediated neuronal death and have prolonged effective time windows of protection compared to other neuroprotective strategies. Therefore, ASICs represent a potential therapeutic target for limiting ischemic brain injury. To fully capitalize on the therapeutic potential of ASIC the molecular mechanisms mediating ASIC-dependent neuroprotection must be uncovered. The most established model of ASIC1a-dependent death involves plasma membrane activation others, however, have suggested the importance of ASIC1a regulation of mitochondrial function. We find that ASIC1a is localized to crude mitochondrial extracts and that H2O2 mediated death is exacerbated by ASIC1a overexpression in NS20Y cells and attenuated in ASIC1a KO hippocampal neurons. Our data has also shown that the N-terminal intracellular region of ASIC1a, and not just ion conduction, is required for ASICs role in H2O2-mediated cell death. Determining how ASIC1a regulates mitochondrial function will further define ASICs role in neuroprotection and identify new strategies to target ASIC1a for therapeutic advantage. Our central hypothesis is that ASIC1a control of H2O2 cell death involves the N-terminus ASIC1a, regulation of mPTP opening, and control of mitochondrial function in a manner independent of ion conduction. To test this hypothesis, we will define the mechanisms governing ASIC1a regulation of mitochondrial function and elucidate ASIC1as role in H202 mediated death. The outcome of the proposed work will solidify the role of ASIC1a in regulating mitochondrial function and clarify the role of ASIC in pathological conditions such as ischemia and neurodegenerative diseases as well as in physiological function contributing to synaptic plasticity, behavior and neuronal signaling.

Keywords: ASIC, Mitochondria