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

Va Northern California Health Care Sys, Mather CA

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Abstract

Emerging evidence indicates that nitric oxide (NO) is involved in cardiac ?1 adrenergic receptor (?1AR) stimulation of cardiac function. We propose that scaffold protein SAP97 plays a critical role in regulation of cardiac ?1AR-induced NOS1-NO signaling cascade via organizing a ?1AR- 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 ?1AR 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 ?1AR-induced NO signaling in heart. Aim 2. SAP97 maintains the integrity of ?1AR-SAP97-NOS1 signalosome to preserve cardiac function. Aim 3. GRK5 promotes desensitization of ?1AR-NO signaling via disruption of the receptor-SAP97 signalosome in heart failure.