The mechanical performance of the heart is determined by its intrinsic contractile properties and is subject to counterbalancing regulation by the autonomic nervous system. While a-adrenergic stimulation increases pump function, cholinergic stimulation decreases it by reducing the conductance of the L-type Ca2+ channel (ICa-L) previously elevated by cAMP (""""""""accentuated antagonism""""""""). Two different G proteins, Go and Gi-2, have been implicated to be absolutely required for this effect, but their exact role and interplay as well as the signaling mechanisms involved are still poorly defined. We have preliminary data suggesting that Go protein may also regulate Ca2+ cycling and force generation by altering excitation contraction (E-C) coupling and the responsiveness of the myofilaments to Ca2+. The overall goal of this investigation is to define the signaling mechanisms that link Go and/or Gi2 protein activation to the muscarinic regulation of ventricular Ca2+ fluxes and contractile function and to test the hypothesis that selective interference with this pathway can be utilized to enhance contractile function in vivo.
The Specific Aims are: (1) to test the hypothesis that expression of activated Gao regulates Ca2+ cycling and cell shortening in the ventricular myocardium by increasing (rather than decreasing) E-C coupling gain and myofilament responsiveness to Ca2+ in concert to its blunting effect on ICa-L, (2) to test whether cell-permeable peptide import can be adapted for introduction of dominant negative inhibitory peptides into adult ventricular cardiocytes as an alternative and possible improvement to adenoviral gene transfer, (3) to test the hypotheses that Go and Gi2 proteins act in concert as mediators of M2-receptor effects on ICa-L, Ca2+ cycling and contractility and that both Galpha and Gbetagamma contribute to this effect (4) to test the hypothesis that interference with Go and/or Gi-mediated signal transduction in the ventricular myocardium can be utilized to enhance ventricular contractile function. Muscarinic """"""""accentuated antagonism"""""""" is of physiological importance both under normal and pathophysiological conditions. A better understanding of the processes involved in muscarinic receptor-mediated opposition of beta-adrenergic stimulation and blunting of contractile function may form the basis for therapeutic interventions aimed at the long-term autonomic input to the heart through a so far underexplored mechanism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072174-02
Application #
6766969
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Przywara, Dennis
Project Start
2003-07-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$365,160
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Zhang, Peng; Su, Jialin; King, Michelle E et al. (2011) Regulator of G protein signaling 2 is a functionally important negative regulator of angiotensin II-induced cardiac fibroblast responses. Am J Physiol Heart Circ Physiol 301:H147-56
Zhu, Ming; Gach, Agnieszka A; Liu, GongXin et al. (2008) Enhanced calcium cycling and contractile function in transgenic hearts expressing constitutively active G alpha o* protein. Am J Physiol Heart Circ Physiol 294:H1335-47
Hao, Jianming; Michalek, Christina; Zhang, Wei et al. (2006) Regulation of cardiomyocyte signaling by RGS proteins: differential selectivity towards G proteins and susceptibility to regulation. J Mol Cell Cardiol 41:51-61
Zhang, Wei; Anger, Thomas; Su, Jialin et al. (2006) Selective loss of fine tuning of Gq/11 signaling by RGS2 protein exacerbates cardiomyocyte hypertrophy. J Biol Chem 281:5811-20