Analog Signalling with ‘Digital’ Molecular Switches

Abstract

Molecular switches, such as the protein kinase CaMKII, play a fundamental role in cell signalling by decoding inputs into either high or low states of activity; because the high activation state can be turned on and persist after the input ceases, these switches have earned a reputation as digital. Although this on/off, binary perspective has been valuable for understanding long timescale synaptic plasticity, accumulating experimental evidence suggests that the CaMKII switch can also control plasticity on short timescales. To investigate this idea further, a non-autonomous, nonlinear ordinary differential equation, representative of a general bistable molecular switch, is analyzed. The results suggest that switch activity in regions surrounding either the high- or low-stable states of activation could act as a reliable analog signal, whose short timescale fluctuations relative to equilibrium track instantaneous input frequency. The model makes intriguing predictions and is validated against previous work demonstrating its suitability as a minimal representation of switch dynamics; in combination with existing experimental evidence, the theory suggests a multiplexed encoding of instantaneous frequency information over short timescales, with integration of total activity over long timescales.\n\nAuthor SummaryBistable molecular switches can decode cellular inputs into distinct high- or low-states of persistent enzymatic activity. Although this on-off, digital perspective is valuable for long timescales, I suggest that short timescale fluctuations of switch activity around either stable state acts as an analog signal that reliably encodes instantaneous input frequency. A minimal model and theory make predictions about the molecular switch CaMKII, synaptic plasticity and burst detection.