Shaping Signals

Abstract

Although keeping up with them can present difficulty for some human brains, it is evident that there are not enough distinct signaling mechanisms to account for the elaborate range of regulatory events that are controlled in a living organism. Neves et al. show one way in which fine-tuning of the same signaling pathway can allow distinct patterns of control. They examined the way in which cell shape impacts a classical signaling pathway from the β-adrenergic receptor through the second messenger adenosine 3′,5′-monophosphate (cAMP) to activation of mitogen-activated protein kinases (MAPKs) in neurons. Neves et al. used a combination of mathematical modeling of the system with measurements of temporal and spatial dynamics of signaling in isolated mouse hippocampal neurons with fluorescence resonance energy transfer imaging techniques. Their results show that the presence of adenylate cyclase activated by β-adrenergic receptors at the cell surface, with phosphodiesterase activity (which degrades cAMP) in the cytosol, along with other properties of the system, led to activation of gradients of signaling through cAMP to MAPKs. Furthermore, in part because the surface-to-volume ratio is very different in the narrow dendrites of a neuron compared with that in the neuronal cell body, there was a distinctly stronger signal in the dendrites than in the cell body, even though receptors are evenly distributed on the surface of the cell. Modeling indicated that the negative regulators would be key factors in controlling the size of microdomains of activation and propagation of spatially distinct signals through the pathway, and experimental manipulations verified this, with pharmacological inhibition of phosphodiesterase 4 allowing MAP kinase activation in the cell body as well as the dendrites. Kholodenko and Kolch provide commentary. S. R. Neves, P. Tsokas, A. Sarkar, E. A. Grace, P. Rangamani, S. M. Taubenfeld, C. M. Alberini, J. C. Schaff, R. D. Blitzer, I. I. Moraru, R. Iyengar, Cell shape and negative links in regulatory motifs together control spatial information flow in signaling networks. Cell 133 , 666-680 (2008). [PubMed] B. N. Kholodenko, W. Kolch, Giving space to cell signaling. Cell 133 , 566-567 (2008). [PubMed]