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Signaling in Small Subcellular Volumes. I. Stochastic and Diffusion Effects on Individual Pathways

National Centre for Biological Sciences, Tata Institute of Fundamental Research, GKVK Campus, Bangalore, India

Correspondence: Address reprint requests to Upinder S. Bhalla, National Centre for Biological Sciences, TIFR, GKVK Campus, Bangalore 560065, India. Tel.: 91-80-2363-6420 ext. 3230; Fax: 91-80-2363-6662; E-mail: bhalla{at}ncbs.res.in.

Many cellular signaling events occur in small subcellular volumes and involve low-abundance molecular species. This context introduces two major differences from mass-action analyses of nondiffusive signaling. First, reactions involving small numbers of molecules occur in a probabilistic manner which introduces scatter in chemical activities. Second, the timescale of diffusion of molecules between subcellular compartments and the rest of the cell is comparable to the timescale of many chemical reactions, altering the dynamics and outcomes of signaling reactions. This study examines both these effects on information flow through four protein kinase regulatory pathways. The analysis uses Monte Carlo simulations in a subcellular volume diffusively coupled to a bulk cellular volume. Diffusion constants and the volume of the subcellular compartment are systematically varied to account for a range of cellular conditions. Each pathway is characterized in terms of the probabilistic scatter in active kinase levels as a measure of "noise" on the pathway output. Under the conditions reported here, most signaling outcomes in a volume below one femtoliter are severely degraded. Diffusion and subcellular compartmentalization influence the signaling chemistry to give a diversity of signaling outcomes. These outcomes may include washout of the signal, reinforcement of signals, and conversion of steady responses to transients.

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