Abstract

L-type voltage dependent calcium channels (VDCCs) are critical components in the regulation of cardiac function. The kinetic characteristics of these channels, which are important in controlling heart rate and force of contraction, are defined by the primary sequence of the four subunits that make up each channel. The objectives of this proposal are to determine the intracardiac distribution of the three beta subunits of L-type VDCCs present in the heart, and to determine the role of the beta subunit in the regulation of the L-type VDCC present in working myocardium.
The specific aims are; 1) to isolate and characterize murine cDNA and genomic clones from the beta2 and beta3 subunit genes, 2) to determine the distribution of the beta1, beta2 and beta3 subunits by in situ hybridization and immunohistochemical detection in heart sections. 3) use gene targeting, to produce a mouse that lacks the beta subunit that is predominantly expressed in working myocardium, and 4) to characterize the effect of this beta null mutation on the L-type VDCC of cardiac myocytes and on the physiology of the intact animal. Specifically modified beta subunits will be introduced into either beta null myocytes or beta null animals to determine their effect on the regulation of the cardiac L-type VDCC.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL047053-04
Application #
6272908
Study Section
Project Start
1998-01-01
Project End
1998-12-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Druckenbrod, Noah R; Powers, Patricia A; Bartley, Christopher R et al. (2008) Targeting of endothelin receptor-B to the neural crest. Genesis 46:396-400
Brickson, S; Fitzsimons, D P; Pereira, L et al. (2007) In vivo left ventricular functional capacity is compromised in cMyBP-C null mice. Am J Physiol Heart Circ Physiol 292:H1747-54
Stelzer, Julian E; Larsson, Lars; Fitzsimons, Daniel P et al. (2006) Activation dependence of stretch activation in mouse skinned myocardium: implications for ventricular function. J Gen Physiol 127:95-107
Stelzer, Julian E; Fitzsimons, Daniel P; Moss, Richard L (2006) Ablation of myosin-binding protein-C accelerates force development in mouse myocardium. Biophys J 90:4119-27
Singla, Dinender K; Hacker, Timothy A; Ma, Lining et al. (2006) Transplantation of embryonic stem cells into the infarcted mouse heart: formation of multiple cell types. J Mol Cell Cardiol 40:195-200
Muthukumarana, Poorni A D S; Lyons, Gary E; Miura, Yuji et al. (2006) Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance. Int Immunopharmacol 6:1993-2001
Stelzer, Julian E; Patel, Jitandrakumar R; Moss, Richard L (2006) Acceleration of stretch activation in murine myocardium due to phosphorylation of myosin regulatory light chain. J Gen Physiol 128:261-72
Stelzer, Julian E; Patel, Jitandrakumar R; Moss, Richard L (2006) Protein kinase A-mediated acceleration of the stretch activation response in murine skinned myocardium is eliminated by ablation of cMyBP-C. Circ Res 99:884-90
Balijepalli, Ravi C; Foell, Jason D; Hall, Duane D et al. (2006) Localization of cardiac L-type Ca(2+) channels to a caveolar macromolecular signaling complex is required for beta(2)-adrenergic regulation. Proc Natl Acad Sci U S A 103:7500-5
Stelzer, Julian E; Dunning, Sandy B; Moss, Richard L (2006) Ablation of cardiac myosin-binding protein-C accelerates stretch activation in murine skinned myocardium. Circ Res 98:1212-8

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