Signaling in small subcellular volumes. I. Stochastic and diffusion
effects on individual pathways.
U. Bhalla. Biophys. J.87 (2):
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.