Abstract
Molecular switches, such as the protein kinase CaMKII, play a fundamental role in cell signaling 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 longer timescales.
Highlights
Many cellular inputs lead to transient changes in cytosolic calcium (Ca2+) levels, generating temporally complex signals that reflect a wealth of information (Berridge et al, 2003)
The model interpretation and results presented here are centered on CaMKII and synaptic plasticity, the reader is encouraged to consider the broader implications for instantaneous frequency coding with other molecular switches, such as mitogen-activated protein kinases (Xiong and Ferrell, 2003; Thomas and Huganir, 2004)
A main goal of this study was to extend the frequency coding idea of De Koninck and Schulman (1998) in a generic switch model that captures the qualitative behavior of CaMKII, but focuses on fast timescale dynamics instead of slow timescales (Box 1)
Summary
Many cellular inputs lead to transient changes in cytosolic calcium (Ca2+) levels, generating temporally complex signals that reflect a wealth of information (Berridge et al, 2003). A celebrated example of a Ca2+ decoder is the protein kinase Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII; Box 1), which can be driven by transient levels of cytosolic Ca2+ into either high or low states of switch-like activity. Once bound to the Ca2+-CaM complex, the kinase’s ability to cooperatively autophosphorylate can produce two distinct stable states: either high or low levels of enzymatic activation. This paper proposes that CaMKII’s principal role is to meaningfully transmit information via its short term dynamics rather than store it permanently within levels of autonomously activated switch
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