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OCT3 gated intracellular β 1 AR activation enhances excitation‐contraction coupling in heart
Author(s) -
Wang Ying,
Zhao Meimi,
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.s1.06524
Subject(s) - intracellular , endoplasmic reticulum , serca , chemistry , contractility , contraction (grammar) , myocyte , medicine , extracellular , microbiology and biotechnology , biophysics , endocrinology , biology , biochemistry , atpase , enzyme
Rationale β 1 AR‐adrenergic receptor (β 1 AR) plays a central role in sympathetic regulation of cardiac excitation‐contraction (EC) coupling. Stimulation of β 1 AR by catecholamines enhances cardiomyocyte contraction and Ca 2+ transient via the cAMP‐protein kinase A (PKA) pathway. Organic cation transporter 3 (OCT3) plays a role in cleaning up the extracellular catecholamines and transporting a portion of catecholamine into myocardium. Recent progress found that β1AR is also present at intracellular membranes. However, how the intracellular β1AR was activated, and the role of OCT3 in regulating intracellular β 1 AR signaling and EC‐coupling remains unknown. Objective To characterize the presence and activation of intracellular β 1 AR‐adrenergic receptors and their impact on cardiac EC‐coupling Methods and Results We used a genetic deletion of OCT3 to inhibit the entrance of catecholamine into the cells. We used isolated myocytes to measure β 1 AR‐induced contractility and Ca 2+ transients. We used PKA activity reporters to detect local activation via intracellular β 1 AR. We found that catecholamine‐induced inotropic effects were diminished in OCT3‐knock out hearts. OCT3 deficiency significantly attenuated norepinephrine (NE) induced PKA activities at the sarcoplasmic reticulum, myocyte contractility, and Ca 2+ transient. Additional data show β 1 AR associates with sarco/endoplasmic reticulum Ca 2+ ‐ATPase (SERCA) at the sarcoplasmic reticulum (SR). Inhibition of OCT3 blocked the transportation of NE, and attenuated β 1 AR‐induced PKA activity at the SR and EC‐coupling. Conclusion Our finding demonstrates a previously unrecognized intracellular β 1 AR‐mediated local PKA activity at SR that is gated by OCT3. Upon catecholamine stimulation, this SR‐localized β 1 AR signal plays a critical role in promoting E‐C coupling and cardiac contractile function. Thus, internal β 1 AR signaling may presents a novel therapeutic target in cardiac diseases treatment. Support or Funding Information NIH HL113413VABX009200