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SAP97 mediates local control of cAMP/PKA gradient to regulate L‐type calcium channels in hearts
Author(s) -
Zhao Meimi,
Wang Ying,
Shi Qian,
Xu Bing,
Xiang Yang Kevin
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06731
Subject(s) - microbiology and biotechnology , protein kinase a , chemistry , kinase , biology , medicine , endocrinology
Rationale Heart failure as one of the leading causes of morbidity worldwide is hallmarked by dysregulated myocardial calcium (Ca 2+ ) and cardiomyocyte apoptosis. There exists an urgent unmet need of developing novel therapies for preventing and reversing HF progression by correcting Ca 2+ dysregulation and inhibiting apoptosis. However, the mechanisms underlying Ca 2+ regulation in physiological and pathological conditions remain incompletely elucidated. Objective To identify how a synaptic associated protein 97 (SAP97) controls cardiac intracellular Ca 2+ in both physiological and HF development. Methods and Results We used genetic deletion (cardiomyocyte specific SAP97 knock out mice, SAP97‐cKO) to determine the essential role of SAP97 in regulating the Ca 2+ 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 Ca 2+ 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 Ca 2+ dysregulation. Moreover, genetic deletion of SAP97 enhances cAMP/PKA activity and induces Ca 2+ dysregulation, which promotes cardiomyocyte apoptosis and HF development in mice. Conclusion SAP97 mediated local control of cAMP/PKA gradients regulates LTCC and Ca 2+ homeostasis in failing heart, therefore offer a novel SAP97/PKA/Ca 2+ signaling axis as a therapeutic target for heart failure prevention and treatment. Support or Funding Information This study was supported by NIH grants HL113413 and HL147264 and VA Merit grant 01BX002900 to Y.K.X.