beta2-Adrenergic signaling in human heart: shift from the cyclic AMP to the arachidonic acid pathway.
We have recently established that enhancement of intracellular calcium cycling and contraction in response to beta2-adrenergic receptor (beta2-AR) stimulation exclusively relies on the activation of the cytosolic phospholipase A2 (cPLA2) and arachidonic acid production, via a pertussis toxin-sensitive G protein (possibly Gi), in embryonic chick cardiomyocytes. We aimed to investigate the relevance of the beta2-AR/Gi/cPLA2 pathway in the human myocardium. In left ventricular biopsies obtained from explanted hearts, beta2-AR stimulation exerted either an inhibition of cPLA2 that was insensitive to pertussis toxin (PTX) treatment, or an activation of cPLA2, sensitive to PTX treatment. In right atrial appendages from patients who were undergoing open heart surgery, we demonstrated that beta2-AR-induced activation of cPLA2 was favored in situations of altered beta1-AR and/or beta2-AR/adenylyl cyclase (AC) stimulations. Alterations were characterized by an increase in EC50value of norepinephrine and a decrease in the maximal AC activation in response to zinterol, respectively. Quantitative reverse transcription-polymerase chain reaction analyses highlighted a positive correlation between the expression of AC5 and AC6 mRNAs in human cardiac atria, which suggested that functional alterations in AC responses were unlikely to be related to changes in the AC5/AC6 mRNA ratio. In addition, the shift from the cyclic AMP to the arachidonic acid pathway was not supported at the transcriptional level by opposite regulation of AC and cPLA2mRNAs expression. This study gives the first evidence of the recruitment of cPLA2by beta2-ARs in the human heart and suggests that the Gi/cPLA2pathway could substitute for a deficient Gs/AC pathway in mediating beta2-AR responses.
Pavoine
Catherine
C
INSERM Unité 581, Hôpital Henri Mondor, 94010 Créteil, France. pavoine@im3.inserm.fr
Behforouz
Niloufar
N
Gauthier
Chantal
C
Le Gouvello
Sabine
S
Roudot-Thoraval
Francoise
F
Martin
Catherine Rucker
CR
Pawlak
Andre
A
Feral
Chloe
C
Defer
Nicole
N
Houel
Remi
R
Magne
Sandrine
S
Amadou
Aissata
A
Loisance
Daniel
D
Duvaldestin
Philippe
P
Pecker
Francoise
F
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D020517:Atrial Appendage; D000242:Cyclic AMP / Q000378:metabolism*; D054513:Group IV Phospholipases A2; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D012333:RNA, Messenger / Q000032:analysis; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013223:Statistics as Topic
D007527:Isoenzymes; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D016718:Arachidonic Acid; D000242:Cyclic AMP; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; C419510:adenylyl cyclase type V