verbatim): The function of electrically excitable cells depends on expressing appropriate levels of a variety of voltage-gated ion channels. This is particularly important in the heart because aberrant ion channel activity can promote the incidence of arrhythmias and sudden death. In the current funding period, we showed that hormones and renovascular hypertension, which is associated with hypertrophy, regulate cardiac voltage-gated potassium (Kv) channel gene expression. Furthermore, we discovered two post-translational effects that control expression of Kv channels. Here we will continue to study these mechanisms that affect expression of cardiac Kv channels. First, we have discovered that native Kvb2 subunits that were previously shown to interact with the N-terminus of Kv1 family channels are associated with Kv4.3 channels. This association requires the C-terminal region of Kv4.3 and enhances protein expression and activity of these transient outward current channels.
Aim 1 will determine the molecular basis of the novel interaction, and elucidate how the auxiliary subunit increases channel expression. Second, we have identified a three amino acid motif near the C-terminus of Kv1 channels that governs cell surface expression. Deletion of the motif, which occurs in some genetic diseases, inhibits complete glycosylation and localization of channels in the plasma membrane. Furthermore, natural variations in the motif account for many differences among wild type Kv1 family members.
Aim 2 will explore how the VXXSL motif governs processing and surface expression of Kv1 channels. Third, we have found that the hypertrophy inducers phenylephrine and Angiotensin II downregulate Kv4.3 mRNA and protein in cultured cardiomyocytes. Although both of these agents activate Gq-coupled receptors, it appears that they use distinct mechanisms to change the expression of the channel.
Aim 3 will determine the molecular and signaling mechanisms used by phenylephrine and Angiotensin II to reduce K4.3 gene transcription and mRNA stability. These studies will identify and elucidate novel mechanisms that control Kv channel expression. The understanding of such mechanisms may aid in the development of drugs to regulate channel expression with the goal of reducing the incidence of arrhythmias and sudden death.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055312-09
Application #
6799215
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Wang, Lan-Hsiang
Project Start
1996-08-01
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2006-07-31
Support Year
9
Fiscal Year
2004
Total Cost
$293,039
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Hewes, Randall S (2008) The buzz on fly neuronal remodeling. Trends Endocrinol Metab 19:317-23
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
Zhou, Chaoming; Ziegler, Chandra; Birder, Lori A et al. (2006) Angiotensin II and stretch activate NADPH oxidase to destabilize cardiac Kv4.3 channel mRNA. Circ Res 98:1040-7
Grishin, Anatoly; Ford, Henri; Wang, Jin et al. (2005) Attenuation of apoptosis in enterocytes by blockade of potassium channels. Am J Physiol Gastrointest Liver Physiol 289:G815-21
Zaks-Makhina, Elena; Kim, Yonjung; Aizenman, Elias et al. (2004) Novel neuroprotective K+ channel inhibitor identified by high-throughput screening in yeast. Mol Pharmacol 65:214-9
Hahn, Junghyun; Tse, Tonia E; Levitan, Edwin S (2003) Long-term K+ channel-mediated dampening of dopamine neuron excitability by the antipsychotic drug haloperidol. J Neurosci 23:10859-66
Wang, Lin; Takimoto, Koichi; Levitan, Edwin S (2003) Differential association of the auxiliary subunit Kvbeta2 with Kv1.4 and Kv4.3 K+ channels. FEBS Lett 547:162-4
Pal, Sumon; Hartnett, Karen A; Nerbonne, Jeanne M et al. (2003) Mediation of neuronal apoptosis by Kv2.1-encoded potassium channels. J Neurosci 23:4798-802
Zhang, T T; Takimoto, K; Stewart, A F et al. (2001) Independent regulation of cardiac Kv4.3 potassium channel expression by angiotensin II and phenylephrine. Circ Res 88:476-82

Showing the most recent 10 out of 23 publications