Activation of alpha/1-adrenergic receptors (AR) is an important initiator of the cardiac hyper-trophic response, which culminates in a characteristic set of genetic and morphologic changes. Two types of alpha/1-AR are expressed in cardiac myocytes, the alpha/1A-and alpha/1B-AR subtypes. Both the alpha/1A- and alpha/1B-AR subtypes couple to G proteins composed of alphabetagamma subunits, which produce bifurcating signals through alpha- and betagamma-mediated regulation of downstream effectors. Our recent data suggest that through alpha- and betagamma-mediated regulation of downstream effectors. Our recent data suggest that activation of both alpha/1A and alpha/1B-AR subtypes and coupling through both G protein alpha- and betagamma-mediated signals are required to elicit all features of the hypertrophic response. To test this hypothesis, the following specific aims will be addressed: 1) To determine the roles of the alpha/1A- and alpha/1B-AR subtypes in activation of different signaling pathways, and ultimately, different biological endpoints associated with cardiac hypertrophy; 2) To identify the regions of the alpha/1A- and alpha/1B-AR subtypes that are responsible for differential activation of signaling pathways; 3) To examine the contributions of the various G protein alpha and betagamma in reproducing activation of different signaling pathways, and ultimately, different biological responses; and 4) To determine the functional interactions of the alpha/1A- and alpha/1B-AR subtypes with distinct combinations of G protein alphabetagamma subunits. The approach will be to manipulate potential components in the signaling pathways between the alpha/1A-AR subtype and phospholipase C (PLC) and the alpha/1B-AR subtype and mitogen activated protein kinases (MAPK/JNK/P38) in a regulated fashion, using a combination of genetics and reverse genetics approaches. Then, the PLC and MAPK/JNK/p38 signaling pathways will be reexamined for their dependence on the targeted components. Morphologic and gene expression changes, which represent the endpoints of signaling pathways, will also be examined for their dependence on the targeted components. These studies are critical for the design of new therapeutic strategies aimed at enhancing or counteracting alpha/1-AR subtype specific effects in the heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049278-10
Application #
6476940
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Reinlib, Leslie
Project Start
1993-01-01
Project End
2004-05-31
Budget Start
2001-12-01
Budget End
2004-05-31
Support Year
10
Fiscal Year
2002
Total Cost
$247,149
Indirect Cost
Name
Weis Center for Research-Geisinger Clinc
Department
Type
DUNS #
079161360
City
Danville
State
PA
Country
United States
Zip Code
17822
McWhinney, C D; Hansen, C; Robishaw, J D (2000) Alpha-1 adrenergic signaling in a cardiac murine atrial myocyte (HL-1) cell line. Mol Cell Biochem 214:111-9
McWhinney, C; Wenham, D; Kanwal, S et al. (2000) Constitutively active mutants of the alpha(1a)- and the alpha(1b)-adrenergic receptor subtypes reveal coupling to different signaling pathways and physiological responses in rat cardiac myocytes. J Biol Chem 275:2087-97
Wenham, D; Rahmatullah, R J; Rahmatullah, M et al. (1997) Differential coupling of alpha1-adrenoreceptor subtypes to phospholipase C and mitogen activated protein kinase in neonatal rat cardiac myocytes. Eur J Pharmacol 339:77-86
Hansen, C A; Schroering, A G; Robishaw, J D (1995) Subunit expression of signal transducing G proteins in cardiac tissue: implications for phospholipase C-beta regulation. J Mol Cell Cardiol 27:471-84
Hansen, C A; Joseph, S K; Robishaw, J D (1994) Ins 1,4,5-P3 and Ca2+ signaling in quiescent neonatal cardiac myocytes. Biochim Biophys Acta 1224:517-26
Hansen, C A; Schroering, A G; Carey, D J et al. (1994) Localization of a heterotrimeric G protein gamma subunit to focal adhesions and associated stress fibers. J Cell Biol 126:811-9
Ray, K; Robishaw, J D (1994) Cloning and sequencing of a rat heart cDNA encoding a G-protein beta subunit related to the human retinal beta 3 subunit. Gene 149:337-40
Robishaw, J D; Hansen, C A (1994) Structure and function of G proteins mediating signal transduction pathways in the heart. Alcohol Clin Exp Res 18:115-20