Somatodendritic Kv2.1 channels are unique among voltage-gated ion channels in that, while having a broad and robust expression in neurons across mammalian brain, they play an exceptional conditional role in regulating neuronal excitability. Previous studies have shown that Kv2.1 in hippocampal pyramidal neurons appears to be relatively uninvolved in regulating neuronal excitability under conditions of low levels of neuronal activity, but becomes actively engaged under periods of high frequency firing, and in response to seizures and hypoxic/ischemic insults. This leads to homeostatic suppression of neuronal excitability that contributes to neuroprotection. The dramatic transformation in Kv2.1 is mediated through dynamic and reversible activity-dependent changes in Kv2.1 phosphorylation, which impacts the localization and gating of Kv2.1 channels in neurons. This proposal is aimed at determining the molecular mechanism underlying regulation of Kv2.1 localization by phosphorylation state, the respective contribution of phosphorylation-dependent changes in Kv2.1 localization versus voltage-dependent gating in the observed Kv2.1-mediated suppression of neuronal excitability under conditions of high levels of neuronal activity, the signaling pathway whereby suppression of neuronal activity leads to enhanced phosphorylation of Kv2.1, and the effects of genetic Kv2.1 knockdown/knockout in vivo on the sensitivity of animals to seizures and hypoxia, and their subsequent recovery. These studies will yield important insights into the physiological and pathological regulation of Kv2.1 channels, which are key regulators of neuronal excitability in mammalian neurons. Moreover, they will provide important new information on the interaction of Kv channel cytoplasmic domains with intracellular signaling pathways that is crucial to integrating membrane excitability with neuronal physiology under both physiological and pathophysiological conditions.

Public Health Relevance

This study aims to better understand basic mechanisms controlling brain function. It focuses on neuronal ion channels and their regulatory enzymes that are important targets for developing new therapeutics for epilepsy and stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042225-12
Application #
8288271
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Silberberg, Shai D
Project Start
2001-07-24
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$498,037
Indirect Cost
$171,594
Name
University of California Davis
Department
Physiology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Vacher, Helene; Trimmer, James S (2011) Diverse roles for auxiliary subunits in phosphorylation-dependent regulation of mammalian brain voltage-gated potassium channels. Pflugers Arch 462:631-43
Trimmer, James S (2011) How native cells regulate their ion channels. Semin Cell Dev Biol 22:131

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