ACID-SENSING ION CHANNELS: TARGETS FOR NEUROPEPTIDE MODULATION AND NEURONAL DAMAGE

Acid-sensing ion channels (ASICs) are proton-gated channels expressed in neurons in the central and peripheral nervous systems. These ion channels are sensors for extracellular pH and contribute to a variety of normal functions including learning and memory, seizure termination, fear, anxiety, and pain. Additionally, ASICs mediate neuron death and axon degeneration during pathological conditions such as ischemic stroke, inflammation, and traumatic injury. My thesis work began focused on ASICs in the peripheral nervous system. In rodent sensory neurons ASICs contribute to sensory transduction and pain. However, little was known about human ASIC channels in sensory neurons. In an effort to address this disparity, I cloned and characterized a novel human ASIC1 transcript variant (human ASIC1b). I discovered that this variant forms functional channels and is expressed in dorsal root ganglia. Furthermore, I discovered that, unlike its rodent homolog, human ASIC1b displays a non-inactivating sustained current and is permeable to calcium. These experiments are the first report of a human ASIC channel homologous to rodent ASIC1b and identify critical characteristics of the channel that may be vital for the function of ASIC1b in humans, particularly in pain. Due to the role of ASIC in neuronal damage in the central nervous system, I became interested in understanding how ASIC modulated damage in the peripheral nervous system, a question that has been largely overlooked. Therefore, I set out to determine how acidosis and ASICs affect peripheral neurons. I discovered that acidosis results in decreased axonal complexity that is dependent on both ASIC1 and ASIC2. For the first time, this work established that ASICs may contribute to peripheral axon morphology. Furthermore, this has implications for many peripheral nervous system diseases where ischemia and inflammation are present and contribute to acidosis.In addition to my work on peripheral ASICs, I also studied mechanisms of ASIC1a neuropeptide modulation. Modulation of ASIC can potentiate or inhibit its activity and therefore may affect physiological and pathological roles of ASIC. Yet, the mechanism of peptide modulation of ASIC is unknown. I have discovered a potential binding site and effector site that contribute to peptide modulation. These discoveries suggest a novel model for peptide modulation of ASIC and provide essential information for targeted drug design.Taken together, my work addresses important gaps in our knowledge of ASICs in two major areas. First, my work identified a human homolog of ASIC1b that displays unique channel characteristics. These characteristics are likely critical for ASIC1b function in humans and must be considered, especially since studies in animal models will overlook their role. Furthermore, I have shown that peripheral ASICs are capable of altering axon morphology of sensory neurons following prolonged acidosis, and this may relate to a variety of peripheral nervous system diseases. Finally, I identified a binding site and potential mechanism for peptide modulation of ASIC channels. This work has furthered our understanding of peptide modulation of ASIC activity and establishes a foundation essential for drug-design to target ASIC activity and reduce acid-induced neuronal damage in the central and peripheral nervous systems.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Integrated Biomedical Science Graduate Program

Grantor dc:publisher

The Ohio State University

Year dc:date

2013

Author dc:creator

• Frey, Erin N.

Contributors dc:contributor

• Askwith, Candice

• Biomedical Research
• Neurosciences
• acid sensing ion channels
• acidosis
• ischemia
• dynorphin
• opioid peptides
• axon degeneration, neuron death, structure function of ion channels
• RFamides
• ASICs

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=osu1365777374

OAI identifier oai:identifier

oai:etd.ohiolink.edu:osu1365777374