The role of protein kinase A and A-kinase anchoring proteins in modulating T-cell activation: progress and future directions.

Protein kinase A (PKA) is a broad-specificity serine/threonine protein kinase whose spatial and temporal regulation is maintained through interactions with A-kinase anchoring proteins (AKAPs). Subcellular localization of AKAPs through unique targeting domains provides a mechanism by which PKA can respond to localized microdomains of cyclic AMP (cAMP) and phosphorylate nearby substrates. For nearly 40 years, cAMP has been known to be a potent modulator of the immune system. cAMP levels are regulated by G-protein-coupled receptors, adenylyl cyclases (AC), and phosphodiesterases (PDEs). This review discusses recent progress made in the discovery of PKA substrates in T lymphocytes and in the identification of AKAPs in T lymphocytes. Because PKA is activated by cAMP, generation and maintenance of cAMP in T cells is also discussed. These findings are framed in the context of understanding the complexity of cAMP and, thus, PKA signaling and are intended to provide the reader with an overview of current literature, as well as an awareness of questions and concerns to consider.