Original Research ARTICLE
Analog Signalling with ‘Digital’ Molecular Switches
- 1Stanford Bio-X, Stanford University, United States
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.
Keywords: molecular switches, frequency coding, stochastic resonance, Cellular computation, CaMKII, synaptic plasiticty, Burst detection, Hill function
Received: 18 Jul 2018;
Accepted: 31 Oct 2018.
Edited by:Vito Di Maio, Istituto di Scienze Applicate e Sistemi Intelligenti "Eduardo Caianiello" (ISASI), Italy
Reviewed by:Joaquín J. Torres, University of Granada, Spain
Ingie Hong, The Johns Hopkins Hospital, Johns Hopkins Medicine, United States
Copyright: © 2018 Clarke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Stephen E. Clarke, Stanford Bio-X, Stanford University, Stanford, CA 94305, California, United States, email@example.com