β₂-Adrenergic Signaling in Human Heart: Shift from the Cyclic AMP to the Arachidonic Acid Pathway

Abstract

We have recently established that enhancement of intracellular calcium cycling and contraction in response to ␤ 2 -adrenergic receptor (␤ 2 -AR) stimulation exclusively relies on the activation of the cytosolic phospholipase A 2 (cPLA 2 ) 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 ␤ 2 -AR/Gi/cPLA 2 pathway in the human myocardium. In left ventricular biopsies obtained from explanted hearts, ␤ 2 -AR stimulation exerted either an inhibition of cPLA 2 that was insensitive to pertussis toxin (PTX) treatment, or an activation of cPLA 2 , sensitive to PTX treatment. In right atrial appendages from patients who were undergoing open heart surgery, we demonstrated that ␤ 2 -AR-induced activation of cPLA 2 was favored in situations of altered ␤ 1 -AR and/or ␤ 2 -AR/adenylyl cyclase (AC) stimulations. Alterations were characterized by an increase in EC 50 value 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 cPLA 2 mRNAs expression. This study gives the first evidence of the recruitment of cPLA 2 by ␤ 2 -ARs in the human heart and suggests that the Gi/cPLA 2 pathway could substitute for a deficient Gs/AC pathway in mediating ␤ 2 -AR responses.

Stress Induces a Switch of Intracellular Signaling in Sensory Neurons in a Model of Generalized Pain

“…Thus, in heart muscle cells, ␤ 2 -adrenegic receptor signaling can switch from G s to G i (Daaka et al, 1997;Hasseldine et al, 2003;Hill and Baker, 2003;Magocsi et al, 2007), and signaling from G i to mediators known to be upstream of PKC (Herrlich et al, 1996;Daaka et al, 1997;Steinberg, 1999;Mackay and Mochly-Rosen, 2001;Pavoine et al, 2003;Pavoine and Defer, 2005) or to PKC (Fraser et al, 2000;Otani et al, 2003;Paruchuri and Sjolander, 2003) have been reported.…”

D-Amphetamine Stimulates D2Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats

“…These receptors, like D 2 -like receptors, can be coupled to PLA 2 activation and AA release (Berg et al, 1998;Garcia and Kim, 1997;KurraschOrbaugh et al, 2003;Pavoine et al, 2003;Qu et al, 2003). However, raclopride's ability to block k* increments following 2.5 mg/kg D-amphetamine (Table 2) indicates that the increments did not directly involve serotonin or epinephrine-initiated signaling.…”

“…Dopaminergic, serotonergic and noradrenergic receptors can be coupled by G-proteins to different effector enzymes, including phospholipase A 2 (PLA 2 ). Phospholipase A 2 activation releases arachidonic acid (AA,) from membrane phospholipids (Axelrod, 1990;Garcia and Kim, 1997;Nilsson et al, 1998;Pavoine et al, 2003;Vial and Piomelli, 1995). Arachidonic acid and its eicosanoid products are important second messengers that can influence membrane excitability, regional cerebral blood flow (rCBF), gene transcription, mood, and sleep (Chen and Bazan, 2005;Fitzpatrick and Soberman, 2001;Niwa et al, 2000;Rapoport and Bosetti, 2002;Shimizu and Wolfe, 1990;Wang et al, 2005).…”

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

“…Semi-quantitative RT-PCR was carried out on a Light Cycler (Roche Diagnostic), as previously described [35]. Oligonucleotide primers (MWG Biotech) were as follows: Rat 18S, 5'-GTAACCCGTTGAACCCCATT-3' (sense) and 5'-CCATCCAATCGGTAGTAGCG-3' (antisense); rat ANP, 5'-AGCGAGCAGACCGATGAAGC-3' (sense) and 5'-GCAGAGTGGGAGAGGTAAGGC-3' (antisense); rat ßMHC, 5'-ATTCTCCTGCTGTTTCTTTACTTG-3' (sense) and 5'-TGACTTTGCCACCCTCTCG-3' (antisense).…”