Emerging evidence indicates that nitric oxide (NO) is involved in cardiac β1 adrenergic receptor (β1AR) stimulation of cardiac function. We propose that scaffold protein SAP97 plays a critical role in regulation of cardiac β1AR-induced NOS1-NO signaling cascade via organizing a β1AR- NOS1 signalosome. This pathway is necessary for regulation of cardiac contractile function. We also hypothesize that G-protein kinase 5 (GRK5) promotes phosphorylation of cardiac β1AR PDZ motif and dissociation of the receptor from the SAP97-organized signalosome for activation of NOS1-NO signaling and promotes desensitization of receptor signaling in cardiac diseases. We will test the hypotheses with the following aims. Aim 1. SAP97 regulates β1AR-induced NO signaling in heart. Aim 2. SAP97 maintains the integrity of β1AR-SAP97-NOS1 signalosome to preserve cardiac function. Aim 3. GRK5 promotes desensitization of β1AR-NO signaling via disruption of the receptor-SAP97 signalosome in heart failure.