Introduction

The stimulation of cell membrane receptors provides specific information that is conveyed throughout the cell via a network of signal transduction pathways. One of the best-characterized pathways involves the diffusible second messenger cAMP. Since its discovery in 1958, many components of the cAMP pathway have been identified and characterized. Most often, cAMP signaling is initiated by hormone or neurotransmitter binding to G-protein-coupled receptors (GPCRs). Receptor stimulation causes the dissociation of Ga subunit from G^ subunits. In turn, Gas activates adenylyl cyclase, a family of integral membrane proteins that catalyzes the synthesis of cAMP from ATP. The most common target of cAMP is the cAMP-dependent protein kinase A (PKA), although other effectors such as cyclic nucleotide-gated channels and the Rapl-guanine nucleotide exchange factor protein directly activated by cAMP (Epac) should be noted. PKA catalyzes the phosphorylation of an array of proteins located throughout the cell. cAMP signaling is terminated by phosphodiesterases that hydrolyze cAMP to 5'-AMP and phos-phatases that dephosphorylate target proteins. Additionally, cAMP generation is opposed by cell membrane receptor-mediated activation of Gai, which inhibits adenylyl cyclase. While this pathway clearly defines the basic mechanics of cAMP signaling, it also presents a picture of the PKA enzyme happily phosphorylating all targets under any conditions of elevated cAMP. Research over the last 30 years has decidedly demonstrated this is not the case, giving rise to the question of how specificity of phosphorylation is maintained. While the molecular mechanisms providing for specificity are not fully understood, new evidence suggests that individual signaling units or "signalosomes" consisting of adenylyl cyclases, cAMP effectors, and phosphodiesterases may account for the spacial-temporal activation of PKA. Importantly, the molecular glue that holds these signalsomes together are the scaffolding proteins A-kinase anchoring proteins (AKAPs). This chapter will highlight the role of AKAPs in the compartmentalization of cAMP and PKA signaling and will suggest how manipulation of AKAP complexes may be used to alter PKA signaling.

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