Exchange activity is regulated principally by cytosolic Na+, Ca2+, and PIP2. However, the properties of these modes of regulation that have emerged from excised patch studies appear to be poorly suited to regulating exchange activity on a beat-to-beat basis. Here we summarize recent findings from our lab indicating that (a) allosteric activation by Ca2+ exhibits hysteresis, (b) elevated concentrations of cytosolic Na+ induce a mode of activity that no longer requires regulatory Ca2+ activation, and (c) the requirement for PIP2 is reduced or eliminated after allosteric Ca2+ activation. Our results suggest that exchange activity in cardiac myocytes may be regulated by the time-integral of Ca2+ transients occurring over multiple beats.
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