BETA1 AND BETA2 ADRENOCEPTOR SIGNALING IN CARDIAC MYOCYTE

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DESCRIPTION (provided by applicant): Beta Adrenoceptors (Beta ARs) signaling is finely regulated to control cardiovascular function in response to sympathetic nervous system input (norepinephrine) and to adrenaline (epinephrine) from the adrenal gland. In animal hearts, two highly homologous Beta ARs (1Beta AR and 2Beta AR) are stimulated by catecholamines to enhance contractility and heart rate. Chronic stimulation of cardiac Beta ARs by elevated circulating catecholamines as well as decreased cardiac 1Beta AR density is clinically associated with heart failure. The primary functions attributed to GPCRs are ligand binding and G-protein coupling. However, the specific and diversified functional properties of GPCRs in vivo involve kinetic receptor conformational changes for binding different partners in signaling complexes, and the localization of receptor signaling complexes in cell type- specific manner. We hypothesize that norepinephrine and epinephrine can activate distinct signaling pathways for both 1Beta AR and 2Beta AR in cardiac myocytes. We have chosen the neonatal cardiac myocyte isolated from the Beta AR gene deficienct mice as a model system to study the functional roles of ligand- receptor interactions in differentiated cells. The goals of this proposal are (1) to characterize 1Beta AR and 2 Beta AR subtype-specific signaling by different agonists in neonatal myocytes, (2) define the cellular and biochemical properties of 1Beta AR and 2Beta AR under norepinephrine and epinephrine stimulation in cardiac myocytes, (3) to characterize the subcellular distribution of 1Beta AR and 2Beta AR, and other signaling molecules under norepinephrine and epinephrine stimulation in cardiac myocytes, (4) to identify receptor interaction domains and their targeted proteins, and to characterize the receptor signaling complex formation and stability upon agonist stimulation. A better understanding of agonist-induced AR conformation change for the organization of signaling complexes may facilitate new drug designs and suggest new clinical applications in treating various cardiovascular diseases.