Voltage-dependent potassium channels (Kv) dynamically regulate intrinsic neuronal excitability. Increasing evidence suggests that Kv2.1 channels play an especially prominent role in homeostatic plasticity and in modulating excitability and calcium entry during repetitive firing. Thus, the broad, long-term objective of this proposal is to characterize the role that Kv2.1 channels play in controlling hyperexcitability associated with alcohol withdrawal. These studies will employ a well-characterized organotypic hippocampal slice culture model of alcohol withdrawal and techniques including confocal imaging, immunohistochemistry, electrophysiology, and biochemical assays.
The specific aims are to: [1] determine if blocking or knocking-down Kv2.1 channels modulate the frequency of action potential firing during ethanol withdrawal, and [2] to test the hypothesis that changes in Kv2.1 modulation of excitability will be reflected as changes in membrane localization and phosphorylation of the channel. Findings from these studies may implicate a novel therapeutic target for possible drug design to treat the severity of alcohol withdrawal and, potentially, relapse. ? ? ?
| Mulholland, Patrick J; Carpenter-Hyland, Ezekiel P; Woodward, John J et al. (2009) Ethanol disrupts NMDA receptor and astroglial EAAT2 modulation of Kv2.1 potassium channels in hippocampus. Alcohol 43:45-50 |
| Mulholland, P J; Luong, N T; Woodward, J J et al. (2008) Brain-derived neurotrophic factor activation of extracellular signal-regulated kinase is autonomous from the dominant extrasynaptic NMDA receptor extracellular signal-regulated kinase shutoff pathway. Neuroscience 151:419-27 |
| Mulholland, Patrick J; Carpenter-Hyland, Ezekiel P; Hearing, Matthew C et al. (2008) Glutamate transporters regulate extrasynaptic NMDA receptor modulation of Kv2.1 potassium channels. J Neurosci 28:8801-9 |
| Mulholland, Patrick J; Chandler, L Judson (2007) The thorny side of addiction: adaptive plasticity and dendritic spines. ScientificWorldJournal 7:9-21 |
