The long-term objective of this proposal is to understand the molecular mechanisms that regulate the function of mammalian A-type K+ channels. These K+ channels activate and inactivate rapidly in response to membrane depolarization, and one of their main functions is to control the neuronal interspike interval in episodes of repetitive firing. Thus, A-type K+ channels directly influence neuronal signal coding that underlies such complex mental processes as learning, memory and other cognitive functions. Two distinct cloned A-type K+ channels will be investigated: mouse brain channels encoded by mKv4.1 and human brain channels encoded by hKv3.4. They activate at membrane potentials negative or positive to the neuronal firing threshold, respectively.The mechanisms that regulate the function of these K+ channels have not been explored. A combination of recombinant DNA methodology (e.g., heterologous expression and mutagenesis in vitro) and electrophysiology (voltage-clamp and patch-clamp recording) will be used to address three aspects: First, the biophysical properties of A-type K+ channels encoded by mKv4.1, at the macroscopic and single channel levels. This information will serve as the basis for understanding regulation of channel function. Second, the molecular mechanisms of regulation of mouse and human A-type K+ channels by protein kinase C (PKC). Specific questions to address here are: i) how activation of PKC controls gating of specific K+ channels; ii) mapping of the phosphorylation site(s) involved; and iii) the significance of PKC as regulator of distinct A-type K+ channels in the nervous system. Third, the mechanisms that may regulate gating of A-type K+ channels (mKv4.1) in their native environment. Specifically exploring: i) how single K+ channels are fine tuned by putative native factors; and ii) strategies that may reveal the structural channel domains involved. Studying the molecular mechanisms that regulate the function of A-type K+ channels may enhance our understanding of brain functions impaired in neurological and psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032337-08
Application #
6393642
Study Section
Special Emphasis Panel (ZRG1-MDCN-3 (01))
Program Officer
Stewart, Randall
Project Start
1993-12-15
Project End
2003-01-31
Budget Start
2001-05-01
Budget End
2003-01-31
Support Year
8
Fiscal Year
2001
Total Cost
$331,490
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Wang, Guangyu (2017) Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BKCa channels. Metallomics 9:634-645
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Schwenk, Jochen; Zolles, Gerd; Kandias, Nikolaos G et al. (2008) NMR analysis of KChIP4a reveals structural basis for control of surface expression of Kv4 channel complexes. J Biol Chem 283:18937-46
Dougherty, Kevin; De Santiago-Castillo, Jose A; Covarrubias, Manuel (2008) Gating charge immobilization in Kv4.2 channels: the basis of closed-state inactivation. J Gen Physiol 131:257-73

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