Potassium channels control the function of excitable cells such as neurons, smooth muscle cells and cardiac myocytes. Potassium channel regulation is also important in programmed cell death in a variety of cell types. Although a great deal is understood about the function and acute modulation of potassium channels, little is known about long-term control of potassium channel function. Yet, manipulating potassium channel expression in vascular smooth muscle cells, cardiac myocytes and neurons could be a valuable therapeutic approach for controlling high blood pressure and reducing the incidence of cardiac arrhythmias and epileptic seizures. Here we pursue three aims focused on our ongoing studies of potassium channel expression and activity.
Aim 1 will determine how Angiotensin II (Ang II) acts on cardiac myocytes to downregulate Kv4.3 channel expression. Experiments will test the hypothesis Ang II acts via NADPH oxidase- generated reactive oxygen species (ROS) to destabilize the 3' untranslated region of the channel messenger RNA.
Aim 2 will determine how a protein and a chemical identified by high throughput screening stimulate Kir2.1 activity. Since total channel expression is unaffected, experiments will focus on whether these two activators affect channel trafficking and function.
Aim 3 will determine how voltage-gated potassium (Kv) channel activity is slowly increased as a critical step in apoptosis. We will determine whether phosphorylation triggers insertion of new homomeric Kv2.1 channels in the cell surface. Furthermore, we will test whether native channels found in vascular smooth muscle and the heart are subject to similar regulation. This proposal will reveal fundamental insights into novel physiological, pharmacological and pathological mechanisms that produce long-term regulation of potassium channel activity in the heart, blood vessels and the brain. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL080632-01A1
Application #
7047452
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wang, Lan-Hsiang
Project Start
2005-12-20
Project End
2009-11-30
Budget Start
2005-12-20
Budget End
2006-11-30
Support Year
1
Fiscal Year
2006
Total Cost
$371,250
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zhou, Chaoming; Ramaswamy, Swarna S; Johnson, Derrick E et al. (2016) Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling. Sci Rep 6:23416
McCord, Meghan C; Aizenman, Elias (2013) Convergent Ca2+ and Zn2+ signaling regulates apoptotic Kv2.1 K+ currents. Proc Natl Acad Sci U S A 110:13988-93
Zhou, Chaoming; Cavolo, Samantha L; Levitan, Edwin S (2012) Delayed endosome-dependent CamKII and p38 kinase signaling in cardiomyocytes destabilizes Kv4.3 mRNA. J Mol Cell Cardiol 52:971-7
Zaks-Makhina, Elena; Li, Hui; Grishin, Anatoly et al. (2009) Specific and slow inhibition of the kir2.1 K+ channel by gambogic acid. J Biol Chem 284:15432-8
Redman, Patrick T; Hartnett, Karen A; Aras, Mandar A et al. (2009) Regulation of apoptotic potassium currents by coordinated zinc-dependent signalling. J Physiol 587:4393-404
Zhou, Chaoming; Vignere, Chandra Z; Levitan, Edwin S (2008) AUF1 is upregulated by angiotensin II to destabilize cardiac Kv4.3 channel mRNA. J Mol Cell Cardiol 45:832-8
Redman, Patrick T; He, Kai; Hartnett, Karen A et al. (2007) Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1. Proc Natl Acad Sci U S A 104:3568-73
Grishin, Anatoly; Li, Hui; Levitan, Edwin S et al. (2006) Identification of gamma-aminobutyric acid receptor-interacting factor 1 (TRAK2) as a trafficking factor for the K+ channel Kir2.1. J Biol Chem 281:30104-11
Salvador-Recatala, Vicenta; Kim, Yonjung; Zaks-Makhina, Elena et al. (2006) Voltage-gated k+ channel block by catechol derivatives: defining nonselective and selective pharmacophores. J Pharmacol Exp Ther 319:758-64
Redman, P T; Jefferson, B S; Ziegler, C B et al. (2006) A vital role for voltage-dependent potassium channels in dopamine transporter-mediated 6-hydroxydopamine neurotoxicity. Neuroscience 143:1-6

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