PT  - JOURNAL ARTICLE
AU  - Stephen E. Clarke
TI  - Analog Signalling with ‘Digital’ Molecular Switches
AID  - 10.1101/256032
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 256032
4099  - http://biorxiv.org/content/early/2018/01/30/256032.short
4100  - http://biorxiv.org/content/early/2018/01/30/256032.full
AB  - 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 binary perspective has been valuable for understanding synaptic plasticity over long timescales, accumulating experimental evidence suggests that molecular switches also control cellular processing on short timescales. To investigate this idea further, a non-autonomous, nonlinear ordinary differential equation, representative of a bistable molecular switch, is analyzed. The existence and uniqueness of model solutions to arbitrary input is proved for both the high and low states of activity. These results suggest that sub-state switch activity is an analog signal that tracks instantaneous input frequency, thereby increasing the capacity for information transfer to downstream cellular targets. Using simple dynamics based on the ubiquitous Hill equation, the model and theory make intriguing predictions about synaptic plasticity and suggest a multiplexed encoding of instantaneous frequency information over short timescales, with integration of total activity over long timescales, helping to reconcile contrasting perspectives presented in the literature.