The Stability of a Stochastic CaMKII Switch: Dependence on the Number of Enzyme Molecules and Protein Turnover

Abstract

Molecular switches have been implicated in the storage of information in biological systems. For small structures such as synapses, these switches are composed of only a few molecules and stochastic fluctuations are therefore of importance. Such fluctuations could potentially lead to spontaneous switch reset that would limit the lifetime of information storage. We have analyzed a model of the calcium/calmodulin-dependent protein kinase II (CaMKII) switch implicated in long-term memory in the nervous system. The bistability of this switch arises from autocatalytic autophosphorylation of CaMKII, a reaction that is countered by a saturable phosphatase-1-mediated dephosphorylation. We sought to understand the factors that control switch stability and to determine the functional relationship between stability and the number of molecules involved. Using Monte Carlo simulations, we found that the lifetime of states of the switch increase exponentially with the number of CaMKII holoenzymes. Switch stability requires a balance between the kinase and phosphatase rates, and the kinase rate must remain high relative to the rate of protein turnover. Thus, a critical limit on switch stability is set by the observed turnover rate (one per 30 h on average). Our computational results show that, depending on the timescale of fluctuations in enzyme numbers, for a switch composed of about 15 CaMKII holoenzymes, the stable persistent activation can span from a few years to a human lifetime.

Spatio-temporal correlations can drastically change the response of a MAPK pathway

“…Perhaps the most studied example is the dual phosphorylation cycle of the MAPK pathway, studied here, but other well-known examples are the Kai system (35), the cyclin-dependent kinase inhibitor Sic1 (36), the Nuclear Factor of Activated T-cells system (37), and the CaM kinase II system (38). Multi-site phosphorylation can lead to an ultrasensitive response (2,3), to a threshold response (34), to bistability (10,38), or synchronise oscillations of phosphorylation levels of individual protein molecules (35), provided the enzymes act via a distributive mechanism. We have studied by using a particle-based model a dual phosphorylation cycle in which the enzymes act according to a distributive mechanism.…”

Structural instability in an autophosphorylating kinase switch

“…So even if there is no bistability as disclosed to us by an analysis of steady states, for finite time the system may maintain a high level of K * , i.e. memory will decay but slowly; see (Miller et al, 2005) for a discussion of this phenomenon.…”

“…I am grateful to an anonymous referee of a previous version of this paper for pointing out the difficulties with using the quasi-steady state approximation and directing my attention to (Buchler et al, 2005) and (Miller et al, 2005).…”

“…One example is provided by ATM, a DNA damage sensor (Bakkenist and Kastan, 2003), another, by the calcium/calmodulindependent protein kinase II (CaMKII), which is considered in (Miller et al, 2005). In that paper, the fact that protein turnover causes the switch to reset itself due to the disappearance of bistability, is clearly acknowledged.…”

Pathway-Specific Bidirectional Regulation of Ca2+/Calmodulin-Dependent Protein Kinase II at Spinal Nociceptive Synapses after Acute Noxious Stimulation

“…Dephosphorylation of CaMKII within the PSD is achieved by PSD-associated protein phosphatase 1 (PP1), which is likely involved in long-term depression and in depotentiation of synapses that have previously undergone LTP (Morishita et al, 2001;Colbran, 2004). Indeed, CaMKII and PP1 have been proposed to form within the PSD a bistable molecular switch that is responsible for the maintenance of LTP (Lisman and Zhabotinsky, 2001;Miller et al, 2005). Notably, however, negative regulation of postsynaptic CaMKII autophosphorylation by neuronal activity has not been demonstrated (Colbran, 2004).…”