Abstract

Large-conductance Ca2+-activated K+ (BK[Ca]) channels play a critical role in the regulation ofl vascular tone, and they are thought to be important mediators of the vasodilatory effects of endothelial derived NO and exogenous vasodilators that activate the cGMP-dependent protein kinase (PKG). Here we propose to address questions that relate to the BK[Ca] channel's activation by PKG in vascular smooth muscle.
In Aim 1 we will address questions having to do with the biochemical mechanism by which the BK[Ca] channel is activated by PKG. Does PKG stably associate with channel? Is a phosphatase required for PKG-mediated BK[Ca] -channel activation? Is the BK[Ca] channel's smooth muscle-specific beta1 subunit required? And does protein kinase C modulate the effect of PKG on the BK channel? In Aim 2 we will focus on the nature of PKG's effect, examining particularly its Ca2+ -dependence and its effect on the response of the channel to a Ca 2+ spark. And in Aim 3 we will examine whether PKGlalpha's leucine zipper domain is required for PKG-mediated modulation of Ca 2+ sparking and BK[Ca] channel opening in vivo. Results from the proposed work are expected to advance our understanding of the regulation of a key ion channel that regulates vasomotion, and they may suggest new strategies for the development of drugs to treat hypertension and ischemic cardiovascular diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL077378-04
Application #
7470532
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$391,384
Indirect Cost

  Institution

Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111

  Publications

Halder, Indrani; Matthews, Karen A; Buysse, Daniel J et al. (2015) African Genetic Ancestry is Associated with Sleep Depth in Older African Americans. Sleep 38:1185-93
Poh, Kian-Keong; Lu, Ping; Qin, Gangjian et al. (2013) Endothelial dysfunction and systemic hypertension by selective cGMP-dependent protein kinase I inhibition using novel cell-penetrating peptide delivered in vivo. Int J Cardiol 167:2114-9
Wang, Guang-rong; Surks, Howard K; Tang, K Mary et al. (2013) Steroid-sensitive gene 1 is a novel cyclic GMP-dependent protein kinase I substrate in vascular smooth muscle cells. J Biol Chem 288:24972-83
Blanton, Robert M; Takimoto, Eiki; Aronovitz, Mark et al. (2013) Mutation of the protein kinase I alpha leucine zipper domain produces hypertension and progressive left ventricular hypertrophy: a novel mouse model of age-dependent hypertensive heart disease. J Gerontol A Biol Sci Med Sci 68:1351-5
Wooten, Eric C; Hebl, Virginia B; Wolf, Matthew J et al. (2013) Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy. Circ Cardiovasc Genet 6:10-8
Joshi, Shreena; Nelson, Mark T; Werner, Matthias E (2012) Amplified NO/cGMP-mediated relaxation and ryanodine receptor-to-BKCa channel signalling in corpus cavernosum smooth muscle from phospholamban knockout mice. Br J Pharmacol 165:455-66
Blanton, Robert M; Takimoto, Eiki; Lane, Angela M et al. (2012) Protein kinase g i? inhibits pressure overload-induced cardiac remodeling and is required for the cardioprotective effect of sildenafil in vivo. J Am Heart Assoc 1:e003731
Halder, Indrani; Kip, Kevin E; Mulukutla, Suresh R et al. (2012) Biogeographic ancestry, self-identified race, and admixture-phenotype associations in the Heart SCORE Study. Am J Epidemiol 176:146-55
Wooten, Eric C; Huggins, Gordon S (2011) Mind the dbGAP: the application of data mining to identify biological mechanisms. Mol Interv 11:95-102
Hill-Eubanks, David C; Werner, Matthias E; Heppner, Thomas J et al. (2011) Calcium signaling in smooth muscle. Cold Spring Harb Perspect Biol 3:a004549

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