Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110γ

Abstract

SUMMARY Adrenergic stimulation of the heart engages cAMP and phosphoinositide second messenger signaling cascades. Cardiac phosphoinositide 3-kinase p110γ participates in these processes by sustaining β-adrenergic receptor internalization through its catalytic function and by controlling phosphodiesterase 3B (PDE3B) activity via an unknown kinase-independent mechanism. We have discovered that p110γ anchors protein kinase A (PKA) through a site in its N-terminal region. Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110γ to inhibit PIP3 production. This provides local feedback control of PIP3 and cAMP signaling events. In congestive heart failure, p110γ is upregulated and escapes PKA-mediated inhibition, contributing to a reduction in β-adrenergic receptor density. Pharmacological inhibition of p110γ normalizes β-adrenergic receptor density and improves contractility in failing hearts.

An entirely specific type I A-kinase anchoring protein that can sequester two molecules of protein kinase A at mitochondria

“…Thus, the PKA anchoring and sphingosine kinase 1 binding may represent independent aspects of SKIP function that reside within the same polypeptide chain. This concept is reminiscent of how other cardiac PKA anchoring proteins such as AKAPLbc and PI3 kinase γ seem to operate as they also encode catalytic units for guanine nucleotide exchange and lipid kinase activity, respectively (57,58). Alternatively, our MS evidence that SKIP is recruited into higher order macromolecular complexes within the mitochondrial intermembrane space could enhance PKA phosphorylation of ChChd3 (43) and accommodate an antiapoptotic role for sphingosine kinase 1 (53).…”

Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B

“…Production of cAMP can be stimulated via ␤-adrenergic pathways or inhibited by PDE3B, which is activated by the insulin-signaling cascade. PKA is activated by cAMP, which can activate PDE3B, creating a negative feedback loop (15,16,19) (Fig. 4).…”

A-kinase anchoring proteins: scaffolding proteins in the heart

“…ezrin (36), sphingosine kinase type 1-interacting protein (61,96), gravin (81), synemin (95), myospryn (92), troponin T (109), and the phosphoinositide 3-kinase p110␥ (90) have been shown to be expressed in cardiac tissues (Table 1). In this context, it is now clear that in the heart, AKAP-based transduction complexes play a crucial role in coordinating signaling pathways that control physiological functions such as Ca 2ϩ cycling, cardiac contractility, and action potential duration, as well as pathophysiological processes including arrhythmias, cardiomyocyte hypertrophy, heart failure, and the adaptive response to hypoxia.…”

“…It is now shown that phosphatidylinositol 3-kinase-␥ (PI3K␥) assembles a newly identified signaling complex containing PKA and PDE3B that might regulate ␤-AR expression at the surface of cardiomyocytes (90). In physiological conditions, the ␤-AR/ cAMP pathway leads to the activation of PI3K␥-anchored PKA, which, in turn, phosphorylates PI3K␥ to inhibit its activity (90).…”