Membranes, ions, and clocks: testing the Njus-Sulzman-Hastings model of the circadian oscillator.

Current circadian clock models based on interlocking autoregulatory transcriptional?translational negative feedback loops have arisen out of an explosion of molecular genetic data obtained over the last decade (for review, see Stanewsky, 2003; Young and Kay, 2001). An earlier model of circadian oscillation was based on feedback interactions between membrane ion transport systems and ion concentration gradients (Njus et al., 1974, 1976). This membrane model was posited as a more plausible alternative at the time to the even earlier "chronon" model, which was based on autoregulatory genetic feedback loops (Ehret and Trucco, 1967). The membrane model has been tested in a number of experimental systems by pharmacologically manipulating either ionic gradients across the plasma membrane or ion transport systems, but with inconsistent results. In the meantime, the scope and explanatory power of the genetic models overshadowed inquiries into the role of membrane ion fluxes in clock function. However, several recently developed techniques described in this article have provided a new glimpse into the essential role that membrane ion fluxes play in the mechanism of the core circadian oscillator and indicate that a complete understanding of the clock must include both genetic and membrane-based feedback loops.