Localization of A-kinase through anchoring proteins.

The CAMP signaling pathway-it seems so simple. A hormone binds its receptor, the receptor activates adenylate cyclase via an intermediary G protein, and CAMP is liberated from the intracellular face of the plasma membrane. This first part is relatively straightforward, but the next two steps in the process require a more sophisticated level of molecular organization. First of all, CAMP activates the CAMP-dependent protein kinase (PKA) by binding to the regulatory subunits (R) of the dormant PKA holoenzyme and causes the release of the active catalytic subunit (C). Then comes the mysterious part. Although PKA is a multifunctional enzyme with a broad substrate specificity, hormonal activation of the kinase somehow permits preferential phosphorylation of specific target substrates. Added to this, PKA key substrates are themselves localized in distinct cellular compartments. For example, phosphorylation of membrane-bound neurotransmitter receptorion channels modulates the flow of ions into the cell, while phosphorylation of nuclear transcription factors (e.g. CAMP response element binding protein) alters the activity of certain genes. One hypothesis to account for the selectivity of PKA action is that individual effecters activate particular pools of the kinase which is anchored to subcellular structures. Support for PKA anchoring is provided by evidence that hormonal activation promotes CAMP accumulation in distinct cellular compartments (1) and that PKA subunits are differentially localized (2). Moreover, a family of A-kinase anchor proteins (AKAPs) have been identified which function to tether the type II PKA to specific subcellular structures (3). The scope of this minireview is to focus on recent advances made in several laboratories on discerning the subcellular location of PKA and on the characterization of AKAPs.