Desensitization of beta1 adrenergic receptor-nitric oxide signaling in cardiac diseases

新的证据表明，一氧化氮(NO)参与了心脏β-1肾上腺素能受体 (β1AR)刺激心功能。我们认为，支架蛋白SAP97起着关键的作用 通过组织β1AR-1调节心脏β-1AR诱导的NOS1-NO信号级联反应 1号信号体。这一途径对心脏收缩功能的调节是必要的。我们 还假设G-蛋白激酶5促进心脏β1AR的磷酸化 PDZ基序和SAP97组织的信号小体上受体的解离激活 NOS1-NO信号转导和促进心脏疾病中受体信号的脱敏。 我们将用以下目标来检验这些假设。目的1.SAP97对β-1AR诱导的NO的调节作用 在心里发出信号。目的2.SAP97维持β1AR-SAP97-NOS1信号体的完整性 保护心脏功能。目的3.GRK5通过促进β1AR-NO信号的脱敏 心力衰竭时SAP97受体信号小体的破坏。

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.