β2-Adrenergic receptor signaling in the cardiac myocyte is modulated by interactions with CXCR4.
Chemokines are small secreted proteins with chemoattractant properties that play a key role in inflammation, metastasis, and embryonic development. We previously demonstrated a nonchemotactic role for one such chemokine pair, stromal cell-derived factor-1α and its G-protein coupled receptor, CXCR4. Stromal cell-derived factor-1/CXCR4 are expressed on cardiac myocytes and have direct consequences on cardiac myocyte physiology by inhibiting contractility in response to the nonselective β-adrenergic receptor (βAR) agonist, isoproterenol. As a result of the importance of β-adrenergic signaling in heart failure pathophysiology, we investigated the underlying mechanism involved in CXCR4 modulation of βAR signaling. Our studies demonstrate activation of CXCR4 by stromal cell-derived factor-1 leads to a decrease in βAR-induced PKA activity as assessed by cAMP accumulation and PKA-dependent phosphorylation of phospholamban, an inhibitor of SERCA2a. We determined CXCR4 regulation of βAR downstream targets is β2AR-dependent. We demonstrated a physical interaction between CXCR4 and β2AR as determined by coimmunoprecipitation, confocal microscopy, and BRET techniques. The CXCR4-β2AR interaction leads to G-protein signal modulation and suggests the interaction is a novel mechanism for regulating cardiac myocyte contractility. Chemokines are physiologically and developmentally relevant to myocardial biology and represent a novel receptor class of cardiac modulators. The CXCR4-β2AR complex could represent a hitherto unknown target for therapeutic intervention.
LaRocca
Thomas J
TJ
Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY 10029, USA.
Schwarzkopf
Martina
M
Altman
Perry
P
Zhang
Shihong
S
Gupta
Achla
A
Gomes
Ivone
I
Alvin
Zikiar
Z
Champion
Hunter C
HC
Haddad
Georges
G
Hajjar
Roger J
RJ
Devi
Lakshmi A
LA
Schecter
Alison D
AD
Tarzami
Sima T
ST
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol