Date of Award

5-2012

Document Type

Thesis

Degree Name

Master of Science (MS)

College/School

College of Science and Mathematics

Department/Program

Biology

Thesis Sponsor/Dissertation Chair/Project Chair

Elena Petroff

Committee Member

Vladislav Snitsarev

Committee Member

Julian Keenan

Abstract

Acid Sensing Ion Channels (ASICs) have recently been identified as inhibitors of voltage and calcium gated ion channels (BK) (Petroff et al. 2008), and their overexpression has been shown to reduce seizure elongation and severity in mice (Ziemenn et al.2008). ASICs regulate BK channel activity in accordance with pH variation (Petroff et al. 2008), and seizures are concurrent with increased acidity in the brain (Ziemenn et al. 2008). Influx of Na+ through the ASIC pore domain has been speculated to cause membrane potential repolarization that reduces seizure proliferation (Vukicevic and Kellenburger, 2004), but this is counterintuitive to what is known about Na+ causing membrane potential depolarization (Grunder and Chen 2010). Modifying BK subunits has been shown to produce temporal lobe seizures, paroxysmal dyskinesia, and generalized epilepsy (Alioua et al 2008), indicating repolarization of neuronal membranes plays a significant role in these disorders. In order to examine how ASIC regulation of BK affects repolarization in neuronal synapses, perforated patch clamp was used to examine membrane fluctuation in rat cortical neurons. Postsynaptic repolarization time constraint increased by 154% when buffering was increased from 2.5 mM HEPES to 20 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic), indicating ASIC inhibition of BK can have a dramatic effect on synaptic transmission. Irregularity in normal ASIC function may be an underlying factor in brain disease, and needs to be explored as a target for pharmaceutical control. To date, pharmacological studies have explored blocking Na+ influx through the pore domain of ASICs (Grunder and Chen et al. 2010), but no attention has been given to its ligand regulation of BK. ASIC/BK interactions offer opportunities for new approaches in controlling synaptic transmission in those suffering from seizures.

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