? adrenergic receptors (?ARs) are critical for cardiac function and are linked to HF. Chronic ?1AR-cAMP signaling promotes activation of CaMKII, which is requisite for all the detrimental effects during maladaptive remodeling in heart. However, the mechanism governing this specific signaling regulation by ?1AR in HF development is still incompletely understood.
We aim to reveal a novel supercomplex of cardiac beta1 adrenergic receptor that is orchestrated by scaffold protein SAP97 and connects to L-type calcium channel directly. Moreover, SAP97 also scaffold AKAP79/PKA and PDE4D8 in the complex to ensure rapid and robust regulation of L-type calcium channel in local vicinity, which is essential to maintain rhythmic beat-to- to-beat cardiac contraction during stress response.
We aim to gain insight of regulation of this sophisticated beta1 adrenergic receptor supercomplex in spatially differentiated cardiac myocytes and explore the dissemble and dysfunction of this complex in disease development via promoting cytotoxicity in heart. We hypothesize that GRK5 acts as a molecular switch to turn on Epac-dependent activation of CaMKII. We have generated mice to simulate dissociation of the b1AR-SAP97 complex and to study SAP97-dependent b1AR signaling in physiology and diseases. This study will provide new insight governing the specific b1AR signaling involved in physiology an in HF, and offer GRK5 as a complementary therapeutic target for HF. The hypothesis will be examined in the following aims:
Aim 1. A SAP97 complex facilitates PKA-dependent regulation of EC coupling.
Aim 2. Disruption of b1AR-SAP97 interaction promotes b1AR-induced CaMKII activity.
Aim 3. GRK5 phosphorylation of b1AR at S475 controls the binding of b1AR to SAP97 to gate cardiotoxic CaMKII in HF.
Cardiac beta1 adrenergic receptor plays a key role in rhythmic beat-to-beat contraction in hearts. In this proposed study, we aim to characterize a supercomplex of beta1 adrenergic receptor that conducts rapid and robust regulation of L-type calcium channel within local vicinity via this sophisticated machinery and explore the dissemble and dysfunction of this complex in disease development.
