Swallowing a spider to catch a fly: Ca-calmodulin dynamics in adult cardiomyocytes

The ubiquitous protein calmodulin (CaM) is a chemical intermediate that links a rise of intracellular Ca 2+ concentration to changes in the activity of a series of enzymes. On the face of it, this mechanism seems straight forward, increased intracellular [Ca 2+], for example during the systole of the cardiac cycle, binds to cytoplasmic CaM and the Ca-CaM complex subsequently binds to a series of target proteins to regulate a range of cellular processes including contraction, ion-transport and transcription [ 1 ]. But the reality is far more complex for several reasons. Firstly, there are several examples of Ca-CaM stimulating both the synthetic and degradative pathways of the same metabolite e.g. Ca-CaM stimulates the enzymes adenlylate cyclase and phosphodiesterase [ 2 ]. Secondly, CaM is actively translocated between the nucleus and the cytoplasm over periods of seconds, so the availability of cytoplasmic CaM can vary over the time course of the response [ 3 ]. Thirdly, the affinity of Ca-CaM for the range of target proteins is not constant [ 1 ], a high affinity association would translate to a very efficient transduction between [Ca 2+] increase and target protein activation. A low affinity association between Ca-CaM and target protein would require very high intracellular [Ca 2+] for transduction. Finally, once Ca-CaM bound to the target protein the affinity of Ca for CaM may increase many fold [ 4 ].