Dissertation/Thesis Abstract

Acid-Sensing Ion Channels: Regulation and Physiologic Function
by Cho, Jun-Hyeong, Ph.D., The Ohio State University, 2008, 169; 10630862
Abstract (Summary)

Acid-sensing ion channels (ASICs) are proton (H+)-gated ion channels that produce transient cation currents in response to extracellular acid. ASICs are expressed widely in the brain, and contribute to normal learning and memory as well as ischemic neuronal damage. However, little is known about how ASICs contribute to neuronal function or how ASICs are regulated by endogenous modulators.

For my thesis, I began by investigating the role of sulfhydryl compounds on ASIC activity. I determined that glutathione, of which concentration increases in ischemic brains, potentiated ASIC1a-mediated H+-gated currents by increasing apparent proton sensitivity and slowing channel desensitization. This potentiation of ASIC1a is due to the relief of tonic inhibition by transition metal ions, and the reduction of redox-sensitive residues. These results suggest that endogenous sulfhydryl compounds such as glutathione potentiate ASICs in neurons.

I also investigated how ASICs contribute to synaptic transmission by comparing synaptic responses between wild-type and ASIC knockout hippocampal neurons in microisland culture. I determined that neurons from ASIC1 knockout mice have an increased probability of neurotransmitter release and altered short-term plasticity. Further, transfection of ASIC1a into ASIC1 knockout neurons restored release probability. These results suggest that ASIC1a regulates basal synaptic transmission and short-term plasticity by modulating neurotransmitter release at glutamatergic synapses.

Both ASIC1 and ASIC2 are expressed in the cerebellum including Purkinje cells, which have intrinsic firing property required for normal cerebellar function. I investigated the physiologic role of ASICs in Purkinje cell firing in acute cerebellar slice preparation. Compared to wild-type mice, the tonic firing rate of Purkinje cells was increased significantly in ASIC1/ASIC2 double knockout mice whereas neither ASIC1 knockout nor ASIC2 knockout mice showed any difference. This suggests that both ASIC1 and ASIC2 can contribute to normal cerebellar function by regulating Purkinje cell firing independently.

Together, these studies describe, for the first time, how ASICs are regulated by glutathione, one of the ischemia-related signals, and how ASICs regulate glutamatergic synaptic transmission and tonic firing of cerebellar Purkinje cells. These results provide significant insights on the pathologic mechanism of ischemic neuronal death, and the physiologic roles of ASICs in synaptic function and neuronal excitability.

Indexing (document details)
Advisor: Askwith, Candice
Commitee: Bishop, Georgia, Enyeart, Jack, Saffen, David
School: The Ohio State University
Department: Integrated Biomedical Science
School Location: United States -- Ohio
Source: DAI-B 78/11(E), Dissertation Abstracts International
Subjects: Cellular biology, Biomedical engineering, Biophysics
Keywords: Asic, Cerebellum, Glutathione, Purkinje cell, Synaptic transmission, Zinc
Publication Number: 10630862
ISBN: 978-0-355-01193-7
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