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)
Type
Research Project (R01)
Project #
5R01NS042225-14
Application #
8681546
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Silberberg, Shai D
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Davis
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Davis
State
CA
Country
United States
Zip Code
95618
Kirk, Lyndsey M; Ti, Shu W; Bishop, Hannah I et al. (2016) Distribution of the SynDIG4/proline-rich transmembrane protein 1 in rat brain. J Comp Neurol 524:2266-80
Cáceres, Mónica; Ortiz, Liliana; Recabarren, Tatiana et al. (2015) TRPM4 Is a Novel Component of the Adhesome Required for Focal Adhesion Disassembly, Migration and Contractility. PLoS One 10:e0130540
Thiffault, Isabelle; Speca, David J; Austin, Daniel C et al. (2015) A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization. J Gen Physiol 146:399-410
Trimmer, James S (2015) Subcellular localization of K+ channels in mammalian brain neurons: remarkable precision in the midst of extraordinary complexity. Neuron 85:238-56
Cerda, Oscar; Cáceres, Mónica; Park, Kang-Sik et al. (2015) Casein kinase-mediated phosphorylation of serine 839 is necessary for basolateral localization of the Ca²⁺-activated non-selective cation channel TRPM4. Pflugers Arch 467:1723-32
Cobb, Melanie M; Austin, Daniel C; Sack, Jon T et al. (2015) Cell Cycle-dependent Changes in Localization and Phosphorylation of the Plasma Membrane Kv2.1 K+ Channel Impact Endoplasmic Reticulum Membrane Contact Sites in COS-1 Cells. J Biol Chem 290:29189-201
Bishop, Hannah I; Guan, Dongxu; Bocksteins, Elke et al. (2015) Distinct Cell- and Layer-Specific Expression Patterns and Independent Regulation of Kv2 Channel Subtypes in Cortical Pyramidal Neurons. J Neurosci 35:14922-42
King, Anna N; Manning, Colleen F; Trimmer, James S (2014) A unique ion channel clustering domain on the axon initial segment of mammalian neurons. J Comp Neurol 522:2594-608
Tilley, Drew C; Eum, Kenneth S; Fletcher-Taylor, Sebastian et al. (2014) Chemoselective tarantula toxins report voltage activation of wild-type ion channels in live cells. Proc Natl Acad Sci U S A 111:E4789-96
Trimmer, James S (2014) Ion channels and pain: important steps towards validating a new therapeutic target for neuropathic pain. Exp Neurol 254:190-4

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