cAMP-stimulated protein phosphatase 2A activity associated with muscle A kinase-anchoring protein (mAKAP) signaling complexes inhibits the phosphorylation and activity of the cAMP-specific phosphodiesterase PDE4D3.

The concentration of the second messenger cAMP is tightly controlled in cells by the activity of phosphodiesterases. We have previously described how the protein kinase A-anchoring protein mAKAP serves as a scaffold for the cAMP-dependent protein kinase PKA and the cAMP-specific phosphodiesterase PDE4D3 in cardiac myocytes. PKA and PDE4D3 constitute a negative feedback loop whereby PKA-catalyzed phosphorylation and activation of PDE4D3 attenuate local cAMP levels.

The mAKAPbeta scaffold regulates cardiac myocyte hypertrophy via recruitment of activated calcineurin.

mAKAPbeta is the scaffold for a multimolecular signaling complex in cardiac myocytes that is required for the induction of neonatal myocyte hypertrophy. We now show that the pro-hypertrophic phosphatase calcineurin binds directly to a single site on mAKAPbeta that does not conform to any of the previously reported consensus binding sites. Calcineurin-mAKAPbeta complex formation is increased in the presence of Ca(2+)/calmodulin and in norepinephrine-stimulated primary cardiac myocytes.

The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain.

A-kinase anchoring proteins (AKAPs) influence the spatial and temporal regulation of cAMP signaling events. Anchoring of PKA in proximity to certain adenylyl cyclase (AC) isoforms is thought to enhance the phosphorylation dependent termination of cAMP synthesis. Using a combination of immunoprecipitation and enzymological approaches, we show that the plasma membrane targeted anchoring protein AKAP9/Yotiao displays unique specificity for interaction and the regulation of a variety of AC isoforms.

The mAKAP signalosome and cardiac myocyte hypertrophy.

Cardiac hypertrophy is regulated by a large intracellular signal transduction network. Each of the many signaling pathways in this network contributes uniquely to the control of cell growth. In the last few years, it has become apparent that multimolecular signaling complexes or 'signalosomes' are important for mediating crosstalk between different signaling pathways.

Dynamic regulation of cAMP synthesis through anchored PKA-adenylyl cyclase V/VI complexes.

Spatiotemporal organization of cAMP signaling begins with the tight control of second messenger synthesis. In response to agonist stimulation of G protein-coupled receptors, membrane-associated adenylyl cyclases (ACs) generate cAMP that diffuses throughout the cell. The availability of cAMP activates various intracellular effectors, including protein kinase A (PKA).

The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling.

Maladaptive cardiac hypertrophy can progress to congestive heart failure, a leading cause of morbidity and mortality in the United States. A better understanding of the intracellular signal transduction network that controls myocyte cell growth may suggest new therapeutic directions. mAKAP is a scaffold protein that has recently been shown to coordinate signal transduction enzymes important for cytokine-induced cardiac hypertrophy.

Orchestration of synaptic plasticity through AKAP signaling complexes.

Significant progress has been made toward understanding the mechanisms by which organisms learn from experiences and how those experiences are translated into memories. Advances in molecular, electrophysiological and genetic technologies have permitted great strides in identifying biochemical and structural changes that occur at synapses during processes that are thought to underlie learning and memory. Cellular events that generate the second messenger cyclic AMP (cAMP) and activate protein kinase A (PKA) have been linked to synaptic plasticity and long-term memory.