J., Crane B. (MeAsp)a nonmetabolizable analog of the chemoattractant aspartate ((light gray) upon repeated application of identical actions are shown for every measured cell, sorted by ARHGAP1 rank of their median response (dark gray). Note that and can take negative values due to measurement noise (fig. S2). The cumulative distribution of median response (traced out by the point series) is usually broad, indicating considerable diversity across cells. a.u., arbitrary models. The instantaneous response of a cell to a step stimulus was quantified by the poststimulus activity defined as the FRET signal relative to the steady state: = is the median of the FRET signal over the 3 s during the to dose-response measurements and determine 1/cells using FRET-based methods (= 0.5), is typically determined by measuring dose-response curves (middle), which can vary from cell to cell. Here, we instead measure the distribution of Dorzolamide HCL upon a stimulus of magnitude [((added MeAsp concentration, given in M by bold-faced figures within panels), where sorting cells by their median poststimulus activity (dark gray dots) provides the cumulative distribution of is usually smaller than (0 1). Using the identity illustrated in (A), the cumulative distribution of = 0.5 for each applied stimulus level [on [and other species are arranged in hexagonal arrays of trimers of dimers that respond cooperatively to signals (coupled receptors form signaling teams within which all receptors (and associated kinase molecules) share the same activity says (active or inactive). The free energy difference between the two receptor says is determined not only by the ligand concentration [of receptors. Because of opinions from downstream adaptation enzymes, the value of at constant state, in turn, depends Dorzolamide HCL on the background stimulus level [= and and chemoreceptors have been constrained by a large body of populace FRET data (and affects the response of kinase activity upon a step switch in ligand concentration from [= (1 + exp (and varies across cells. Model 2 (blue dotted lines): is usually fixed, but varies across the populace. In model Dorzolamide HCL 2, is usually fixed and exhibited a tuning of and (for the receptor cognate to the applied ligand stimulus. The model yields excellent fits to the changes in the shape of the is the important ingredient for response diversity, the posttranslational mechanism that accounts for adaptive tuning of that diversity does not require a change in the degree of variance in across cells. Posttranslational receptor modification implements an environment-dependent diversity switch To pinpoint the mechanism responsible for diversity tuning with the MWC model, we focused on the simplest variant (model 1) that reproduced Dorzolamide HCL the observed diversity tuning assuming cell-to-cell variance in only a single parameter, (dotted collection). The measured is in excellent agreement with the model prediction (blue point). All affects diversity in log (contributes strongly to diversity in can be suppressed. We found that the susceptibility O?log (= ?log (= ? (= 0. Because of nonlinearities arising in the allosteric mechanism, the dependence of changes qualitatively as the methylation level crosses (specifically, sets the concentration scale), and therefore, the degree of receptor coupling strongly affects sensitivity. In this regime, the susceptibility O?log (to cause substantial (log (= ? (log (at which the adapted state modification level reaches M MeAsp (Fig. 5A, vertical dashed collection), at which the model predicts an intermediate level of of chemoreceptors (but instead from is usually a coarse-grained parameter that can be affected by both the size and composition of receptor clusters, the likely dominant contribution to its variance is the expression-level ratio Dorzolamide HCL between the two major receptor species Tar and Tsr, which has been shown to vary strongly across cells (cells express five types of chemoreceptors (Tar, Tsr, Tap, Trg, and Aer) that sense a variety of stimuli (to a hypothetical homogenous populace (fig. S13B). As expected from the diversity in the sensitivity due to the variance in in the low-background transmission regime of the coupled two-state receptors (> 1) extends the dynamic range of sensing to lower concentrations due to the 1/scaling of.