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In the vertebrate central nervous system, exploratory filopodia transiently form on dendritic branches to sample the neuronal environment and initiate new trans-neuronal contacts. While much is known about the molecules that control filopodia extension and subsequent maturation into functional synapses, the mechanisms that regulate initiation of these dynamic, actin-rich structures have remained elusive. Here, we find that filopodia initiation is suppressed by recruitment of ArhGAP44 to actin-patches that seed filopodia. Recruitment is mediated by binding of a membrane curvature-sensing ArhGAP44 N-BAR domain to plasma membrane sections that were deformed inward by acto-myosin mediated contractile forces. A GAP domain in ArhGAP44 triggers local Rac-GTP hydrolysis, thus reducing actin polymerization required for filopodia formation. Additionally, ArhGAP44 expression increases during neuronal development, concurrent with a decrease in the rate of filopodia formation. Together, our data reveals a local auto-regulatory mechanism that limits initiation of filopodia via protein recruitment to nanoscale membrane deformations.

Despite large cell-to-cell variations in the concentrations of individual signaling proteins, cells transmit signals correctly. This phenomenon raises the question of what signaling systems do to prevent a predicted high failure rate. Here we combine quantitative modeling, RNA interference, and targeted selective reaction monitoring (SRM) mass spectrometry, and we show for the ubiquitous and fundamental calcium signaling system that cells monitor cytosolic and endoplasmic reticulum (ER) Ca2+ levels and adjust in parallel the concentrations of the store-operated Ca2+ influx mediator stromal interaction molecule (STIM), the plasma membrane Ca2+ pump plasma membrane Ca-ATPase (PMCA), and the ER Ca2+ pump sarco/ER Ca2+-ATPase (SERCA). Model calculations show that this combined parallel regulation in protein expression levels effectively stabilizes basal cytosolic and ER Ca2+ levels and preserves receptor signaling. Our results demonstrate that, rather than directly controlling the relative level of signaling proteins in a forward regulation strategy, cells prevent transmission failure by sensing the state of the signaling pathway and using multiple parallel adaptive feedbacks. [ABSTRACT FROM AUTHOR]

An inability to publish issues of journals at the appointed times is a problem common to many scholarly publishers in developing countries. One solution is to accept and announce a delay by dating a new issue with the actual published date. Another problem is the appearance of some issues out of sequence. This may be due to the desire to produce special thematic issues, which can interfere with the rapid communication of research findings and new ideas. It is also important that reviews of new publications appearing in scholarly journals be up-to-date. The implications for scholarship of delays in publication are considered and the importance of dating articles as well as journal issues is emphasized. [ABSTRACT FROM PUBLISHER]

This chapter describes approaches to make use of dynamic models of cell signaling systems in order to optimize experiments in cell biology. We are particularly focusing on the question of how small molecule inhibitors or activators can best be used to get the most information out of a limited number of experiments when only a handful of molecular species can be measured. One goal addressed by this chapter is to find time course experiments to discriminate between rivaling molecular mechanisms. The other goal is to find experiments that are useful for inferring rate constants, binding affinities, concentrations, and other model parameters from time course data. Both are treated as optimal control problems in which rapid pharmacological perturbation schemes are identified in silico in order to close an experimental cycle from modeling back to the laboratory bench.

Despite large cell-to-cell variations in the concentrations of individual signaling proteins, cells transmit signals correctly. This phenomenon raises the question of what signaling systems do to prevent a predicted high failure rate. Here we combine quantitative modeling, RNA interference, and targeted selective reaction monitoring (SRM) mass spectrometry, and we show for the ubiquitous and fundamental calcium signaling system that cells monitor cytosolic and endoplasmic reticulum (ER) Ca(2+) levels and adjust in parallel the concentrations of the store-operated Ca(2+) influx mediator stromal interaction molecule (STIM), the plasma membrane Ca(2+) pump plasma membrane Ca-ATPase (PMCA), and the ER Ca(2+) pump sarco/ER Ca(2+)-ATPase (SERCA). Model calculations show that this combined parallel regulation in protein expression levels effectively stabilizes basal cytosolic and ER Ca(2+) levels and preserves receptor signaling. Our results demonstrate that, rather than directly controlling the relative level of signaling proteins in a forward regulation strategy, cells prevent transmission failure by sensing the state of the signaling pathway and using multiple parallel adaptive feedbacks.