ALPHA1-ADRENERGIC SIGNALING PATHWAYS IN HEART

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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.