Bimodal Regulation Research Articles

Minerals in the pre-settled coral Stylophora pistillata crystallize via protein and ion changes

Aragonite skeletons in corals are key contributors to the storage of atmospheric CO2 worldwide. Hence, understanding coral biomineralization/calcification processes is crucial for evaluating and predicting the effect of environmental factors on this process. While coral biomineralization studies have focused on adult corals, the exact stage at which corals initiate mineralization remains enigmatic. Here, we show that minerals are first precipitated as amorphous calcium carbonate and small aragonite crystallites, in the pre-settled larva, which then evolve into the more mature aragonitic fibers characteristic of the stony coral skeleton. The process is accompanied by modulation of proteins and ions within these minerals. These findings may indicate an underlying bimodal regulation tactic adopted by the animal, with important ramification to its resilience or vulnerability toward a changing environment.

Galantamine attenuates N,N-dimethyl hydrazine induced neoplastic colon damage by inhibiting acetylcholinesterase and bimodal regulation of nicotinic cholinergic neurotransmission

The present study reveals the effect of galantamine (GAL) against 1, 2-dimethylhydrazine (DMH) induced colon cancer. Wistar albino rats were arbitrarily divided into four groups (n = 8). Group 1 served as normal control (normal saline, 3ml/kg/day, p.o.); group 2, 3 and 4 received DMH (20mg/kg/week, s.c.), for 6 weeks; groups 3 and 4 also received GAL (2 and 4mg/kg/day, p.o) for 6 weeks. DMH treated rats showed decreased heart rate variability (HRV) factors, increased incidence of aberrant crypt foci (ACF), increased thiobarbituric acid reactive substances (TBARs) along with the decrease in the enzymatic activity of superoxide dismutase (SOD) and catalase. Increased levels of inflammatory marker cyclooxygenase (COX) and lipoxygenase (LOX) was also evident in DMH treated animals. The colonic surface architecture was studied using scanning electron microscopy revealed aberrant crypts(X500) and neoplastic nodules (X2000). GAL treatment helped to minimize the ACF count, restored oxidative stress and inflammatory markers favorably. To further validate our results, our study was directed to define the effect of GAL on acetylcholine neurotransmission using a simple model organism, Caenorhabditis elegans (C. elegans). Increased synaptic cholinergic transmission by GAL (32µM) was evident in the worms when studied through aldicarb assay. However, GAL (32µM) treatment negatively modulated α7 nicotinic acetylcholine receptor (α7nAch receptor), when evaluated using the levamisole assay. GAL (32µM) treatment down regulated the genomic expression of ace-1, ace-2 along with unc-29, unc-38, and unc-50 (essential components of α7 nAch receptor). GAL by inhibiting AchE and regulating Alpha7nACh activity can improve cholinergic neurotransmission.

Hox D genes and the fin-to-limb transition: Insights from fish studies.

Genes in the 5' extremity of the HoxD cluster encode DNA-binding transcription factors essential for development of the autopod and digits, regulating primarily gene expression and, consequently, morphogenesis and skeletal differentiation. Comparative studies focused on their expression and regulation have led to the idea that evolution of a bimodal regulation of the HoxD cluster, mainly due to the activation of cis-regulatory units in the centromeric side of the cluster, was a fundamental mechanism that potentiated the fin-to-limb transition in vertebrates. In addition, functional assays demonstrated that increased levels of 5'HoxD genes stimulate the production of additional endochondral bone, while repressing the formation of dermal skeleton distally. Other data have come to light in recent years suggesting that these genes may interfere directly with the production of dermal skeleton components in fish and with the activity of cis-regulatory units involved in the formation of autopod and digits. Finally, increasing evidences suggest that the role of HoxD genes in fin evolution may relate to their ability to change the fate of distal mesenchymal cells conducting them to differentiate into endochondral bone rather than in dermal skeleton. Here, we trace the history of the research concerning the involvement of HoxD genes in the fin-to-limb transition in vertebrates. To this end, we discuss three interconnected topics that have benefited from profound advances in recent years due to comparative analyses and functional assays performed using fish species: (a) comparative HoxD genes expression; (b) comparative HoxD gene transcriptional regulation; and (c) functional characterization of 5'HoxD genes.

Identification of the bimodal transcriptional regulation of SP1 transcription factor in sub-sets of gastric cancer

Identification of the bimodal transcriptional regulation of SP1 transcription factor in sub-sets of gastric cancer

Nup153 Interacts with Sox2 to Enable Bimodal Gene Regulation and Maintenance of Neural Progenitor Cells

Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate-determining transcription factors is unclear. Here we show that thenucleoporin Nup153 interacts with Sox2 in adultNeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes. Binding of Nup153 to gene promoters or transcriptional end sites correlates with increased or decreased gene expression, respectively, and inhibiting Nup153 expression alters open chromatin configurations at its target genes, disrupts genomic localization of Sox2, and promotes differentiation invitro and a gliogenic fate switch invivo. Together, these findings reveal that nuclear structural proteins may exert bimodal transcriptional effects to control cell fate.

Bacterial-Chromatin Structural Proteins Regulate the Bimodal Expression of the Locus of Enterocyte Effacement (LEE) Pathogenicity Island in Enteropathogenic Escherichia coli.

ABSTRACTIn enteropathogenic Escherichia coli (EPEC), the locus of enterocyte effacement (LEE) encodes a type 3 secretion system (T3SS) essential for pathogenesis. This pathogenicity island comprises five major operons (LEE1 to LEE5), with the LEE5 operon encoding T3SS effectors involved in the intimate adherence of bacteria to enterocytes. The first operon, LEE1, encodes Ler (LEE-encoded regulator), an H-NS (nucleoid structuring protein) paralog that alleviates the LEE H-NS silencing. We observed that the LEE5 and LEE1 promoters present a bimodal expression pattern, depending on environmental stimuli. One key regulator of bimodal LEE1 and LEE5 expression is ler expression, which fluctuates in response to different growth conditions. Under conditions in vitro considered to be equivalent to nonoptimal conditions for virulence, the opposing regulatory effects of H-NS and Ler can lead to the emergence of two bacterial subpopulations. H-NS and Ler share nucleation binding sites in the LEE5 promoter region, but H-NS binding results in local DNA structural modifications distinct from those generated through Ler binding, at least in vitro. Thus, we show how two nucleoid-binding proteins can contribute to the epigenetic regulation of bacterial virulence and lead to opposing bacterial fates. This finding implicates for the first time bacterial-chromatin structural proteins in the bimodal regulation of gene expression.

Knockdown of epigenetic transcriptional co-regulator Brd2a disrupts apoptosis and proper formation of hindbrain and midbrain-hindbrain boundary (MHB) region in zebrafish

Brd2 is a member of the bromodomain-extraterminal domain (BET) family of proteins and functions as an acetyl-histone-directed transcriptional co-regulator and recruitment scaffold in chromatin modification complexes affecting signal-dependent transcription. While Brd2 acts as a protooncogene in mammalian blood, developmental studies link it to regulation of neuronal apoptosis and epilepsy, and complete knockout of the gene is invariably embryonic lethal. In Drosophila, the Brd2 homolog acts as a maternal effect factor necessary for segment formation and identity and proper expression of homeotic loci, including Ultrabithorax and engrailed. To test the various roles attributed to Brd2 in a single developmental system representing a non-mammalian vertebrate, we conducted a phenotypic characterization of Brd2a deficient zebrafish embryos produced by morpholino knockdown and corroborated by Crispr-Cas9 disruption and small molecule inhibitor treatments. brd2aMO morphants exhibit reduced hindbrain with an ill-defined midbrain-hindbrain boundary (MHB) region; irregular notochord, neural tube, and somites; and abnormalities in ventral trunk and ventral nerve cord interneuron positioning. Using whole mount TUNEL and confocal microscopy, we uncover a significant decrease, then a dramatic increase, of p53-independent cell death at the start and end of segmentation, respectively. In contrast, using qualitative and quantitative analyses of BrdU incorporation, phosphohistone H3-tagging, and flow cytometry, we detect little effect of Brd2a knockdown on overall proliferation levels in embryos. RNA in situ hybridization shows reduced or absent expression of homeobox gene eng2a and paired box gene pax2a, in the hindbrain domain of the MHB region, and an overabundance of pax2a-positive kidney progenitors, in knockdowns. Together, these results suggest an evolutionarily conserved role for Brd2 in the proper formation and/or patterning of segmented tissues, including the vertebrate CNS, where it acts as a bi-modal regulator of apoptosis, and is necessary, directly or indirectly, for proper expression of genes that pattern the MHB and/or regulate differentiation in the anterior hindbrain.

Bimodal regulation of Dishevelled function by Vangl2 during morphogenesis.

Convergent extension (CE) is a fundamental morphogenetic mechanism that underlies numerous processes in vertebrate development, and its disruption can lead to human congenital disorders such as neural tube closure defects. The dynamic, oriented cell intercalation during CE is regulated by a group of core proteins identified originally in flies to coordinate epithelial planar cell polarity (PCP). The existing model explains how core PCP proteins, including Van Gogh (Vang) and Dishevelled (Dvl), segregate into distinct complexes on opposing cell cortex to coordinate polarity among static epithelial cells. The action of core PCP proteins in the dynamic process of CE, however, remains an enigma. In this report, we show that Vangl2 (Vang-like 2) exerts dual positive and negative regulation on Dvl during CE in both the mouse and Xenopus. We find that Vangl2 binds to Dvl to cell-autonomously promote efficient Dvl plasma membrane recruitment, a pre-requisite for PCP activation. At the same time, Vangl2 inhibits Dvl from interacting with its downstream effector Daam1 (Dishevelled associated activator of morphogenesis 1), and functionally suppresses Dvl→Daam1 cascade during CE. Our finding uncovers Vangl2-Dvl interaction as a key bi-functional switch that underlies the central logic of PCP signaling during morphogenesis, and provides new insight into PCP-related disorders in humans.

Bimodal traffic regulation system: A multi-agent approach

The development of surface public transportation networks is a major issue in terms of ecology, economy and society. Their quality in terms of punctuality and passengers services (regularity between buses) should be improved in order to improve their attractiveness. To do so, cities often use regulation systems at intersections that grant priority to buses. The problem is that each transportation mode has its own characteristics and a dedicated decision support system. Therefore, most of them hardly take into account both public transport vehicles such as buses and private vehicle traffic. This paper proposes a multi-agent model that supports bimodal regulation and preserves monomodal regulation. The objective is to improve global traffic, to reduce bus delays and to improve bus regularity in congested areas of the network. In our approach, traffic regulation is obtained thanks to communication, collaboration and negotiation between heterogeneous agents. We tested our strategy on a complex network of nine junctions. The results of the simulation are presented.

A single three-dimensional chromatin compartment in amphioxus indicates a stepwise evolution of vertebrate Hox bimodal regulation.

The HoxA and HoxD gene clusters of jawed vertebrates are organized into bipartite three-dimensional chromatin structures that separate long-range regulatory inputs coming from the anterior and posterior Hox-neighboring regions. This architecture is instrumental in allowing vertebrate Hox genes to pattern disparate parts of the body, including limbs. Almost nothing is known about how these three-dimensional topologies originated. Here we perform extensive 4C-seq profiling of the Hox cluster in embryos of amphioxus, an invertebrate chordate. We find that, in contrast to the architecture in vertebrates, the amphioxus Hox cluster is organized into a single chromatin interaction domain that includes long-range contacts mostly from the anterior side, bringing distant cis-regulatory elements into contact with Hox genes. We infer that the vertebrate Hox bipartite regulatory system is an evolutionary novelty generated by combining ancient long-range regulatory contacts from DNA in the anterior Hox neighborhood with new regulatory inputs from the posterior side.

Modulation of the Calcium-Dependent Chloride Channel TMEM16A by Extracellular Protons

TMEM16A, the pore forming subunit of the Ca2+-dependent Cl- channel (CaCCs) plays an important role in physiological processes such as fluid secretion, muscular contractility and thermal nociception. This channel is activated in response to increments in intracellular [Ca2+] and membrane depolarization. Previous studies established that endogenous CaCCs are regulated by extracellular protons ([H+]o). In this work the effect of [H+]o on the TMEM16A activity was evaluated using the whole-cell patch clamp technique. Stably transfected HEK293 cells were dialyzed with a solution containing 140 mM Cl- and 0.2 µM Ca2+. We found that [H+]o regulates the chloride current (ICl) in a bimodal manner. Decreasing [H+]o from 10−7.3 to 10−10 M decreased ICl without changing the activation kinetics. In contrast, increasing the [H+]o from 10−7.3 to 10−6 M increased ICl; but a further increase of [H+]o to 10−5, 10−4.5 or 10−4 M reduced ICl to 37% respect to 10−7.3 M. The effect of protons on ICl peaked at 10−5.5 M, were independent of the conformational state (closed or open) of the channel as well as of membrane voltage. The bimodal regulation suggests the existence of two titrable sites with pK values of 7.1 and 5.2, respectively. To verify this we generated the following mutants E362Q, E368Q, E623Q, E624Q, H402Y, H802Y, and H807Y, but none of the mutations prevented the effects of [H+]o. Then to investigate if the effect of [H+]o depended on the degree of TMEM16A activation we dialyzed cells with different [Ca2+]i. Surprisingly we found that increasing the [Ca2+]i produces a strong reduction of the H+ effect, suggesting that extracellular protons regulate TMEM16A by altering the open probability of the channel. Supported by grant 219949 from CONACyT.

The bimodally expressed microRNA miR-142 gates exit from pluripotency.

A stem cell's decision to self-renew or differentiate is thought to critically depend on signaling cues provided by its environment. It is unclear whether stem cells have the intrinsic capacity to control their responsiveness to environmental signals that can be fluctuating and noisy. Using a novel single-cell microRNA activity reporter, we show that miR-142 is bimodally expressed in embryonic stem cells, creating two states indistinguishable by pluripotency markers. A combination of modeling and quantitative experimental data revealed that mESCs switch stochastically between the two miR-142 states. We find that cells with high miR-142 expression are irresponsive to differentiation signals while cells with low miR-142 expression can respond to differentiation cues. We elucidate the molecular mechanism underpinning the bimodal regulation of miR-142 as a double-negative feedback loop between miR-142 and KRAS/ERK signaling and derive a quantitative description of this bistable system. miR-142 switches the activation status of key intracellular signaling pathways thereby locking cells in an undifferentiated state. This reveals a novel mechanism to maintain a stem cell reservoir buffered against fluctuating signaling environments.

Bimodal regulation of an Elk subfamily K+ channel by phosphatidylinositol 4,5-bisphosphate.

Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates Shaker K+ channels and voltage-gated Ca2+ channels in a bimodal fashion by inhibiting voltage activation while stabilizing open channels. Bimodal regulation is conserved in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, but voltage activation is enhanced while the open channel state is destabilized. The proposed sites of PIP2 regulation in these channels include the voltage-sensor domain (VSD) and conserved regions of the proximal cytoplasmic C terminus. Relatively little is known about PIP2 regulation of Ether-á-go-go (EAG) channels, a metazoan-specific family of K+ channels that includes three gene subfamilies, Eag (Kv10), Erg (Kv11), and Elk (Kv12). We examined PIP2 regulation of the Elk subfamily potassium channel human Elk1 to determine whether bimodal regulation is conserved within the EAG K+ channel family. Open-state stabilization by PIP2 has been observed in human Erg1, but the proposed site of regulation in the distal C terminus is not conserved among EAG family channels. We show that PIP2 strongly inhibits voltage activation of Elk1 but also stabilizes the open state. This stabilization produces slow deactivation and a mode shift in voltage gating after activation. However, removal of PIP2 has the net effect of enhancing Elk1 activation. R347 in the linker between the VSD and pore (S4-S5 linker) and R479 near the S6 activation gate are required for PIP2 to inhibit voltage activation. The ability of PIP2 to stabilize the open state also requires these residues, suggesting an overlap in sites central to the opposing effects of PIP2 on channel gating. Open-state stabilization in Elk1 requires the N-terminal eag domain (PAS domain + Cap), and PIP2-dependent stabilization is enhanced by a conserved basic residue (K5) in the Cap. Our data shows that PIP2 can bimodally regulate voltage gating in EAG family channels, as has been proposed for Shaker and HCN channels. PIP2 regulation appears fundamentally different for Elk and KCNQ channels, suggesting that, although both channel types can regulate action potential threshold in neurons, they are not functionally redundant.

Bimodal regulation of genetic competence

Bimodal regulation of genetic competence

αPIX Is a Trafficking Regulator that Balances Recycling and Degradation of the Epidermal Growth Factor Receptor.

Endosomal sorting is an essential control mechanism for signaling through the epidermal growth factor receptor (EGFR). We report here that the guanine nucleotide exchange factor αPIX, which modulates the activity of Rho-GTPases, is a potent bimodal regulator of EGFR trafficking. αPIX interacts with the E3 ubiquitin ligase c-Cbl, an enzyme that attaches ubiquitin to EGFR, thereby labelling this tyrosine kinase receptor for lysosomal degradation. We show that EGF stimulation induces αPIX::c-Cbl complex formation. Simultaneously, αPIX and c-Cbl protein levels decrease, which depends on both αPIX binding to c-Cbl and c-Cbl ubiquitin ligase activity. Through interaction αPIX sequesters c-Cbl from EGFR and this results in reduced EGFR ubiquitination and decreased EGFR degradation upon EGF treatment. However, quantitatively more decisive for cellular EGFR distribution than impaired EGFR degradation is a strong stimulating effect of αPIX on EGFR recycling to the cell surface. This function depends on the GIT binding domain of αPIX but not on interaction with c-Cbl or αPIX exchange activity. In summary, our data demonstrate a previously unappreciated function of αPIX as a strong promoter of EGFR recycling. We suggest that the novel recycling regulator αPIX and the degradation factor c-Cbl closely cooperate in the regulation of EGFR trafficking: uncomplexed αPIX and c-Cbl mediate a positive and a negative feedback on EGFR signaling, respectively; αPIX::c-Cbl complex formation, however, results in mutual inhibition, which may reflect a stable condition in the homeostasis of EGF-induced signal flow.

A Novel Feedback Loop That Controls Bimodal Expression of Genetic Competence.

Gene expression can be highly heterogeneous in isogenic cell populations. An extreme type of heterogeneity is the so-called bistable or bimodal expression, whereby a cell can differentiate into two alternative expression states. Stochastic fluctuations of protein levels, also referred to as noise, provide the necessary source of heterogeneity that must be amplified by specific genetic circuits in order to obtain a bimodal response. A classical model of bimodal differentiation is the activation of genetic competence in Bacillus subtilis. The competence transcription factor ComK activates transcription of its own gene, and an intricate regulatory network controls the switch to competence and ensures its reversibility. However, it is noise in ComK expression that determines which cells activate the ComK autostimulatory loop and become competent for genetic transformation. Despite its important role in bimodal gene expression, noise remains difficult to investigate due to its inherent stochastic nature. We adapted an artificial autostimulatory loop that bypasses all known ComK regulators to screen for possible factors that affect noise. This led to the identification of a novel protein Kre (YkyB) that controls the bimodal regulation of ComK. Interestingly, Kre appears to modulate the induction of ComK by affecting the stability of comK mRNA. The protein influences the expression of many genes, however, Kre is only found in bacteria that contain a ComK homologue and, importantly, kre expression itself is downregulated by ComK. The evolutionary significance of this new feedback loop for the reduction of transcriptional noise in comK expression is discussed. Our findings show the importance of mRNA stability in bimodal regulation, a factor that requires more attention when studying and modelling this non-deterministic developmental mechanism.

Bimodal regulation of ICR1 levels generates self-organizing auxin distribution.

Auxin polar transport, local maxima, and gradients have become an important model system for studying self-organization. Auxin distribution is regulated by auxin-dependent positive feedback loops that are not well-understood at the molecular level. Previously, we showed the involvement of the RHO of Plants (ROP) effector INTERACTOR of CONSTITUTIVELY active ROP 1 (ICR1) in regulation of auxin transport and that ICR1 levels are posttranscriptionally repressed at the site of maximum auxin accumulation at the root tip. Here, we show that bimodal regulation of ICR1 levels by auxin is essential for regulating formation of auxin local maxima and gradients. ICR1 levels increase concomitant with increase in auxin response in lateral root primordia, cotyledon tips, and provascular tissues. However, in the embryo hypophysis and root meristem, when auxin exceeds critical levels, ICR1 is rapidly destabilized by an SCF(TIR1/AFB) [SKP, Cullin, F-box (transport inhibitor response 1/auxin signaling F-box protein)]-dependent auxin signaling mechanism. Furthermore, ectopic expression of ICR1 in the embryo hypophysis resulted in reduction of auxin accumulation and concomitant root growth arrest. ICR1 disappeared during root regeneration and lateral root initiation concomitantly with the formation of a local auxin maximum in response to external auxin treatments and transiently after gravitropic stimulation. Destabilization of ICR1 was impaired after inhibition of auxin transport and signaling, proteasome function, and protein synthesis. A mathematical model based on these findings shows that an in vivo-like auxin distribution, rootward auxin flux, and shootward reflux can be simulated without assuming preexisting tissue polarity. Our experimental results and mathematical modeling indicate that regulation of auxin distribution is tightly associated with auxin-dependent ICR1 levels.

Bimodal regulation of p21waf1 protein as function of DNA damage levels

Human p21Waf1 protein is well known for being transcriptionally induced by p53 and activating the cell cycle checkpoint arrest in response to DNA breaks. Here we report that p21Waf1 protein undergoes a bimodal regulation, being upregulated in response to low doses of DNA damage but rapidly and transiently degraded in response to high doses of DNA lesions. Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21Waf1 on T145 and S146 residues and induces its proteasome-dependent proteolysis. The initial p21Waf1 degradation is then counteracted by the ATM-Chk2 pathway, which promotes the p53-dependent accumulation of p21Waf1 at any dose of damage. We also found that p21Waf1 ablation favors the activation of an apoptotic program to eliminate otherwise irreparable cells. These findings support a model in which in human cells a balance between ATM-Chk2-p53 and the ATR-Chk1 pathways modulates p21Waf1 protein levels in relation to cytostatic and cytotoxic doses of DNA damage.

Potential involvement of Brugia malayi cysteine proteases in the maintenance of the endosymbiotic relationship with Wolbachia

Brugia malayi, a parasitic nematode that causes lymphatic filariasis, harbors endosymbiotic intracellular bacteria, Wolbachia, that are required for the development and reproduction of the worm. The essential nature of this endosymbiosis led to the development of anti-Wolbachia chemotherapeutic approaches for the treatment of human filarial infections. Our study is aimed at identifying specific proteins that play a critical role in this endosymbiotic relationship leading to the identification of potential targets in the adult worms. Filarial cysteine proteases are known to be involved in molting and embryogenesis, processes shown to also be Wolbachia dependent. Based on the observation that cysteine protease transcripts are differentially regulated in response to tetracycline treatment, we focused on defining their role in symbiosis. We observe a bimodal regulation pattern of transcripts encoding cysteine proteases when in vitro tetracycline treated worms were examined. Using tetracycline-treated infertile female worms and purified embryos we established that the first peak of the bimodal pattern corresponds to embryonic transcripts while the second takes place within the hypodermis of the adult worms. Localization studies of the native proteins corresponding to Bm-cpl-3 and Bm-cpl-6 indicate that they are present in the area surrounding Wolbachia, and, in some cases, the proteins appear localized within the bacteria. Both proteins were also found in the inner bodies of microfilariae. The possible role of these cysteine proteases during development and endosymbiosis was further characterized using RNAi. Reduction in Bm-cpl-3 and Bm-cpl-6 transcript levels was accompanied by hindered microfilarial development and release, and reduced Wolbachia DNA levels, making these enzymes strong drug target candidates.

Caveolin-1 Alters the Pattern of Cytoplasmic Ca2+ Oscillations and Ca2+-dependent Gene Expression by Enhancing Leukotriene Receptor Desensitization

Cytoplasmic Ca(2+) oscillations constitute a widespread signaling mode and are often generated in response to stimulation of G protein-coupled receptors that activate phospholipase C. In mast cells, repetitive Ca(2+) oscillations can be evoked by modest activation of cysteinyl leukotriene type I receptors by the physiological trigger, leukotriene C4. The Ca(2+) oscillations arise from regenerative Ca(2+) release from inositol 1,4,5-trisphosphate-sensitive stores followed by Ca(2+) entry through store-operated Ca(2+) channels, and the latter selectively activate the Ca(2+)-dependent transcription factor NFAT. The cysteinyl leukotriene type I receptors desensitize through negative feedback by protein kinase C, which terminates the oscillatory Ca(2+) response. Here, we show that the scaffolding protein caveolin-1 has a profound effect on receptor-driven Ca(2+) signals and downstream gene expression. Overexpression of caveolin-1 increased receptor-phospholipase C coupling, resulting in initially larger Ca(2+) release transients of longer duration but which then ran down quickly. NFAT-activated gene expression, triggered in response to the Ca(2+) signal, was also reduced by caveolin-1. Mutagenesis studies revealed that these effects required a functional scaffolding domain within caveolin-1. Mechanistically, the increase in Ca(2+) release in the presence of caveolin-1 activated protein kinase C, which accelerated homologous desensitization of the leukotriene receptor and thereby terminated the oscillatory Ca(2+) response. Our results reveal that caveolin-1 is a bimodal regulator of receptor-dependent Ca(2+) signaling, which fine-tunes the spatial and temporal profile of the Ca(2+) rise and thereby its ability to activate the NFAT pathway.