Communication Between the Plasma Membrane and Cytosolic Cardiac Pacemakers: A Role for Melatonin?

We review here briefly the essentials of the vertebrate cardiac pacemaking system consisting of the populations of ion channels that drive heartbeat. In addition to the sarcolemmal system, there is a second ion channel-based oscillator consisting centrally of a reciprocating Ca2+ flow between the sarcoplasmic reticulum and the cytosol regulated by release through ryanodine receptors and active return by the Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase. We review the considerable similarity between vertebrate and the fly heart pacemakers. In our work with Drosophila, we have shown that melatonin is capable of increasing the rhythmicity of the fly heart to a remarkable level. This is true even in flies bearing mutations that severely damage ion channels central to the plasma membrane pacemaker. We review here evidence showing that mutations in the gene encoding the fly Calcium ATPase have severe effects on heart function. We present further evidence from our work that melatonin has only a modest effect in reversing these defects. We have hypothesized that melatonin acts by altering the relationship between the sarcolemmal and cytosolic oscillators and cite these and previous findings as provocative in this regard.