Skip to Main Content
 

Global Search Box

 
 
 
 

Files

ETD Abstract Container

Abstract Header

Regulation of ATP-Sensitive Potassium Channels in the Heart

Abstract Details

2009, Doctor of Philosophy, Ohio State University, Pharmacy.

ATP-sensitive potassium channels (KATP channels) link the cellular energy levels to membrane potential and excitability in various cell types like pancreatic β-cells, vascular smooth muscle cells, cardiac myocytes and neurons. In cardiac myocytes, many regulators of sarcKATP channels (Kir6.2/SUR2A) have been identified, but little is known about the subcellular localization of KATP channels which can have a profound impact on the temporal and spatial regulation by its signaling modulators. So, we designed our studies to characterize the localization of KATP channel protein in cardiac myocytes. Using a variety of different techniques on isolated murine cardiomyocytes, we found that majority of cardiac KATP channels are localized to caveolin-enriched membrane microdomains. Whole-cell voltage-clamp recording in both adult and neonatal cardiac myocytes proved that this localization is essential for activation of KATP channel by its modulator adenosine (Chapter 1). We further found that Cav-3 has significant inhibitory effect on KATP channels in recombinant expression system which can be reversed by a scaffolding domain peptide from caveolin-3 protein sequence (CSD) (Chapter 2). This shows a very interesting, dual regulation of KATP channels by caveolins and caveolae. Though caveolae structure ensures that KATP channel modulators are close to the channel proteins for efficient signal transduction, caveolin-3 protein through direct or indirect interaction with channel proteins makes sure that they remain inhibited until required.

In our effort to elucidate the sub-cellular localization of cardiac KATP channels, we also reported a novel finding that a specific protein kinase C (PKC) isoform, PKCε, promotes mitochondrial import of Kir6.2-containing KATP channels from cytosol. These findings were further corroborated with functional data using mitochondrial potential measurement studies. Collectively, our data demonstrated that the localization of cardiac KATP channel can be modulated by specific regulatory pathways, and furthermore furthermore their regulation can be affected by their sub-cellular localization. This provides valuable insight into the mechanisms regulating KATP channels, which have been implicated for cardioprotection under ischemic conditions.

Keli Hu (Advisor)
Lane J. Wallace (Committee Member)
Terry S. Elton (Committee Member)
Dale G. Hoyt (Committee Member)
210 p.

Recommended Citations

Citations

  • Garg, V. (2009). Regulation of ATP-Sensitive Potassium Channels in the Heart [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1238179085

    APA Style (7th edition)

  • Garg, Vivek. Regulation of ATP-Sensitive Potassium Channels in the Heart. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1238179085.

    MLA Style (8th edition)

  • Garg, Vivek. "Regulation of ATP-Sensitive Potassium Channels in the Heart." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1238179085

    Chicago Manual of Style (17th edition)