Inhibitor Protein Kinase A (PKA)

The cAMP-dependent protein kinase (protein kinase A; PKA) pathway is one of the most versatile signaling pathways in eukaryotic cells. Various extracellular signals converge on this signaling pathway through ligand binding to G protein-coupled receptors. Hence, the PKA pathway is tightly regulated at several levels to maintain specificity in the multitude of signal inputs. PKA is composed of two regulatory and two catalytic subunits. In the holoenzyme, the regulatory subunits are bound to the active site of the catalytic subunits, inactivating them. Binding of cAMP to the regulatory subunits causes a conformational change that releases and activates the two catalytic subunits. The active catalytic subunits can then phosphorylate serine and/or threonine residues on the substrates in the cytosol and in the nucleus. When the levels of cAMP begin to fall, the regulatory subunits regain their affinity towards the catalytic subunits and form the inactive holoenzyme. If cAMP levels remain persistently elevated, many cells change their behavior and may either differentiate, proliferate, or undergo apoptosis.

PKA holoenzyme exists in two forms, type I and type II. They contain identical catalytic subunits; however, their regulatory subunits differ (RI or RII dimer). Type I holoenzyme is predominantly cytosolic, whereas type II holoenzyme is compartmentalized to subcellular organelles via specific anchoring proteins. The turnover rate of free type I regulatory subunit is significantly higher than that of type II subunits. When free catalytic subunit is microinjected into the cytoplasm of intact cells, it migrates to the nucleus, whereas the free regulatory subunit remains only in the cytoplasm following microinjection. When both subunits are co-injected, the regulatory subunit blocks the nuclear migration of the catalytic subunit. CREB is a major nuclear target for the catalytic subunit that binds to cAMP response elements (CREs) in the promoter regions of cAMP-responsive genes. Phosphorylation of CREB proteins alters their ability to form dimers and to interact with CREs.

References:
Naviglio, S., et al. 2009. Expert Opin. Ther. Targets. 13, 83. Full article
Skålhegg, B.S. et al. 2005. Curr. Drug Targets. 6, 655. Abstract
Tasken, K, and Aandahl, E.M. 2004. Physiol. Rev. 84, 137. Abstract
Taylor, S.S., et al. 2004. Biochim. Biophys. Acta 1697, 259. Abstract
Skålhegg, B.S., and Tasken, K. 2000. Front. Biosci. 5, 678. Abstract
Spaulding, S.W. 1993. Endocrine Rev. 14, 632. Abstract