SAP97 mediates local control of cAMP/PKA gradient to regulate L‐type calcium channels in hearts

Abstract

RationaleHeart failure as one of the leading causes of morbidity worldwide is hallmarked by dysregulated myocardial calcium (Ca2+) and cardiomyocyte apoptosis. There exists an urgent unmet need of developing novel therapies for preventing and reversing HF progression by correcting Ca2+ dysregulation and inhibiting apoptosis. However, the mechanisms underlying Ca2+ regulation in physiological and pathological conditions remain incompletely elucidated.ObjectiveTo identify how a synaptic associated protein 97 (SAP97) controls cardiac intracellular Ca2+ in both physiological and HF development.Methods and ResultsWe used genetic deletion (cardiomyocyte specific SAP97 knock out mice, SAP97‐cKO) to determine the essential role of SAP97 in regulating the Ca2+ channel activity and how this contributes to the heart failure process. Proximity ligation assay (PLA) and confocal imaging technology were applied to identify a novel SAP97/protein Kinase A (PKA)/ L‐type calcium channel (LTCC) protein machinery complex. We use fluorescence resonance energy transfer (FRET) and living cell imaging to analyze the dynamic spatial changes of Ca2+ homeostasis under the sympathetic adrenergic control of SAP97/LTCC complex. Our study found that a SAP97 binds LTCC and modulates PKA‐dependent LTCC activation via scaffolding PKA and phosphodiesterase 4D8 (PDE4D8) in cardiomyocyte. Disruption of this complex impaired the negative feedback control of cAMP/PKA by PDE4D8, therefore augments PKA‐dependent LTCC activation and promotes Ca2+ dysregulation. Moreover, genetic deletion of SAP97 enhances cAMP/PKA activity and induces Ca2+ dysregulation, which promotes cardiomyocyte apoptosis and HF development in mice.ConclusionSAP97 mediated local control of cAMP/PKA gradients regulates LTCC and Ca2+ homeostasis in failing heart, therefore offer a novel SAP97/PKA/Ca2+ signaling axis as a therapeutic target for heart failure prevention and treatment.Support or Funding InformationThis study was supported by NIH grants HL113413 and HL147264 and VA Merit grant 01BX002900 to Y.K.X.