Multimodal signaling impacting Ca channels regulation in the heart.

The fight—or—flight response in the heart enhances calcium currents that are required for increased force and rate of contraction. The ”textbook” dogma of this mechanism includes direct phosphorylation of the calcium channel protein by protein kinase A (PKA), yet many studies over the years have refuted it. Since protein kinase A is activated, and found in the proximity of the channel, it may phosphorylate some other protein. Rad, a protein that inhibits the calcium channel, was recently discovered to be phosphorylated by PKA. When phosphorylated, Rad no longer inhibits the channel, therefore currents are increased. We found a novel interaction between PKA and the channel itself that may explain how PKA can phosphorylate Rad. We hypothesize that the specific interaction domain on the channel serves as a molecular hub for other proteins as well. In this proposal we wish to explore in depth these molecular interactions so that the mechanism by which the fight—or—flight response increases calcium currents is resolved. Identifying and understanding the role of key molecules in this significant physiologic cardiac response can advance treatment of various cardiac diseases by targeting key (previously unknown) elements.