beta(1)-Adrenergic receptor vs adenylyl cyclase 6 expression in cardiac myocytes: differences in transgene localization and intracellular signaling.

Adenylyl cyclase type 6 (AC6) and the beta(1) adrenergic receptor (beta(1)AR) are pivotal proteins in transmembrane betaAR-signaling in cardiac myocytes. Increased expression of AC6 has beneficial effects on the heart, but increased beta(1)AR expression has marked deleterious effects. Why do these two elements of the betaAR pathway have such different effects? Using adenovirus-mediated gene transfer of the two transgenes in neonatal rat cardiac myocytes, we assessed cellular distribution and performed selected biochemical assays. beta(1)AR was found predominantly in the plasma membrane. In contrast, AC6 was found in the plasma membrane but also was associated with the nuclear envelope, sarcoplasmic reticulum, mitochondria, and cytoplasm. Increased beta(1)AR, but not AC6, increased follistatin expression, p38 phosphorylation, phosphatidylserine translocation to the PM, and apoptosis. In contrast, increased AC6, but not beta(1)AR, inhibited PHLPP2 activity, activated PI3K and Akt, and increased p70S6 kinase phosphorylation and Bcl-2 expression; apoptosis was unchanged. The distribution of AC6 to multiple cellular compartments appears to enable interactions with other proteins (e.g., PHLPP2) and activates cardioprotective signaling (PI3K/Akt). In contrast, beta(1)AR, confined to the plasma membrane, increased phosphatidylserine translocation and apoptosis. These data provide a potential underlying mechanism for the beneficial vs deleterious effects of these two related betaAR-signaling elements.