The Activation of Protein Kinase A by the Calcium-Binding Protein S100A1 Is Independent of Cyclic AMP

[Image: see text] Biochemical and structural studies demonstrate that S100A1 is involved in a Ca(2+)-dependent interaction with the type 2α and type 2β regulatory subunits of protein kinase A (PKA) (RIIα and RIIβ) to activate holo-PKA. The interaction was specific for S100A1 because other calcium-binding proteins (i.e., S100B and calmodulin) had no effect. Likewise, a role for S100A1 in PKA-dependent signaling was established because the PKA-dependent subcellular redistribution of HDAC4 was abolished in cells derived from S100A1 knockout mice. Thus, the Ca(2+)-dependent interaction between S100A1 and the type 2 regulatory subunits represents a novel mechanism that provides a link between Ca(2+) and PKA signaling, which is important for the regulation of gene expression in skeletal muscle via HDAC4 cytosolic–nuclear trafficking.