Targeting P2 receptors in purinergic signaling: a new strategy of active ingredients in traditional Chinese herbals for diseases treatment

Adenosine triphosphate (ATP) and its metabolites adenosine diphosphate, adenosine monophosphate, and adenosine in purinergic signaling pathway play important roles in many diseases. Activation of P2 receptors (P2R) channels and subsequent membrane depolarization can induce accumulation of extracellular ATP, and furtherly cause kinds of diseases, such as pain- and immune-related diseases, cardiac dysfunction, and tumorigenesis. Active ingredients of traditional Chinese herbals which exhibit superior pharmacological activities on diversified P2R channels have been considered as an alternative strategy of disease treatment. Experimental evidence of potential ingredients in Chinese herbs targeting P2R and their pharmacological activities were outlined in the study.

     

Adaptive signaling behavior in stomatopods under varying light conditions

Stomatopod crustaceans (mantis shrimp) are aggressive benthic marine predators with extraordinary color vision. When communicating with conspecifics, many stomatopods display conspicuously colored body areas, often in combination with other types of signals such as motion and chemical cues. Some species occupy wide depth ranges (>30 m), where changing light conditions can influence color perception. To test the potential effects of differing ambient lights on signaling behavior, stomatopods (Gonodactylus smithii) interacted with conspecifics in aquaria, under full-spectrum, high intensity light or light restricted in either spectrum or intensity. During intrasexual and intersexual trials in full-spectrum, high intensity light, animals performed more aggressive acts using colored body parts (meral spread, lunge, strike). Stomatopods used significantly more antennular flicking, and performed aggressive acts at reduced distances under restricted light conditions. To compare the use of antennules in visual and chemical communication, additional experiments showed more antennular flicking in response to chemical stimuli from food or conspecifics compared to seawater controls. This response ceased immediately after ablation of antennular chemoreceptors but returned to pre-treatment levels after 5 days of recovery. These findings suggest that stomatopods can vary their use of signals during conspecific interactions under different photic conditions. These inducible, plastic behavioral responses can potentially improve signal transfer in varying light environments.     

All roads lead to Rome (but some may be harder to travel): SRP-independent translocation into the endoplasmic reticulum

Abstract

Translocation into the endoplasmic reticulum (ER) is the first biogenesis step for hundreds of eukaryotic secretome proteins. Over the past 30 years, groundbreaking biochemical, structural and genetic studies have delineated one conserved pathway that enables ER translocation- the signal recognition particle (SRP) pathway. However, it is clear that this is not the only pathway which can mediate ER targeting and insertion. In fact, over the past decade, several SRP-independent pathways have been uncovered, which recognize proteins that cannot engage the SRP and ensure their subsequent translocation into the ER. These SRP-independent pathways face the same challenges that the SRP pathway overcomes: chaperoning the preinserted protein while in the cytosol, targeting it rapidly to the ER surface and generating vectorial movement that inserts the protein into the ER. This review strives to summarize the various mechanisms and machineries which mediate these stages of SRP-independent translocation, as well as examine why SRP-independent translocation is utilized by the cell. This emerging understanding of the various pathways utilized by secretory proteins to insert into the ER draws light to the complexity of the translocational task, and underlines that insertion into the ER might be more varied and tailored than previously appreciated.     

Subsarcolemmal mitochondrial flashes induced by hypochlorite stimulation in cardiac myocytes

Abstract

Mitochondrial superoxide flash (mitoflash) reflects quantal and bursting superoxide production and concurrent membrane depolarization triggered by transient mitochondrial permeability transition in many types of cells, at the level of single mitochondria. Here we investigate reactive oxygen species (ROS)-mediated modulation of mitoflash activity in cardiac myocytes and report a surprising finding that hypochlorite ions potently and preferentially triggered mitoflashes in the subsarcolemmal mitochondria (SSM), whereas hydrogen peroxide (H₂O₂) elicited mitoflash activity uniformly among SSM and interfibrillar mitochondria (IFM). The striking SSM mitoflash response to hypochlorite stimulation remained intact in cardiac myocytes from NOX2-deficient mice, excluding local NOX2-mediated ROS as the major player. Furthermore, it occurred concomitantly with SSM Ca²⁺ accumulation and local Ca²⁺ and CaMKII signaling played an important modulatory role by altering frequency and unitary properties of SSM mitoflashes. These findings underscore the functional heterogeneity of SSM and IFM and the oxidant-specific responsiveness of mitochondria to ROS, and may bear important ramifications in devising therapeutic strategies for the treatment of oxidative stress-related heart diseases.     

Inhibition of NF-κB signaling interferes with phorbol ester-induced growth arrest of keratinocytes in a TNFR1-independent manner

A skin-specific block in NF-κB signaling leads to hyperproliferation of the keratinocytes, inflammation, and spontaneous development of squamous cell carcinoma (SCC). Here we show that an inhibition of NF-κB signaling in keratinocytes, via the expression of the super-repressor/ degradation-resistant form of the IκBα protein (IκBαDN), interferes with the growth arrest induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). The IκBαDN cells are able to overcome the TPA-induced cell cycle block. Although SCC development as well as hyperproliferation due to IκBαDN expression in keratinocytes is known to require TNFR1 signaling, the effect of IκBαDN on phorbol ester signaling is downstream/independent of TNFR1. These data thus identify an interaction between IκBαDN and the tumor promoter TPA in the growth regulation of keratinocytes. The proposed mechanism is also likely to be significant in the process of cancer development due to NF-κB inhibition.     

Interrogating 7TM receptors: Does texture in the question yield greater texture in the answer?

The key to detecting and classifying drug effect at seven transmembrane (7TM) receptors is the pharmacological assay. Drug discovery had been rooted in testing of molecules on intact animal tissue until technology provided high-throughput binding assays for screening. While this allowed for the testing of large numbers of molecules, it also limited detection to molecules that interfere with the interaction of the receptor with a defined probe (i.e., radioligand). The ability to monitor functional changes in cells (recombinant or natural) provided a huge leap forward. Earlier functional assays were tied to specific signaling pathways (i.e., cyclic AMP and calcium) but now label-free assays in live cells provide the opportunity to detect more ligands and more fully characterize their efficacy. These ideas will be discussed in terms of harnessing the phenomenon of “functional selectivity” for therapeutic advantage.     

Accounting for robustness in modeling signal transduction responses

Abstract

A classical question in systems biology is to find a Boolean model which is able to predict the observed responses of a signaling network. It has been previously shown that such models can be tailored based on experimental data. While fitting a minimum-size network to the experimentally observed data is a natural assumption, it can potentially result in a network which is not so robust against the noises in the training dataset. Indeed, it is widely accepted now that biological systems are generally evolved to be very robust. Therefore, in the present work, we extended the classical formulation of Boolean network construction in order to put weight on the robustness of the created network. We show that our method results generally in more relevant networks. Consequently, considering robustness as a design principle of biological networks can result in more realistic models.     

Cell signaling and receptors with resorcinols and flavonoids: redox,reactive oxygen species,and physiological effects

There have been appreciable numbers of reviews on monophenols, catechols, and hydroquinones. However, the resorcinol class has received less attention. This review deals with resorcinols and flavonoids. Emphasis is on cell signaling in addition to antioxidant (AO) properties and pro-oxidant effects. The apparent dichotomy is rationalized. There is extensive literature dealing with various aspects of cell signaling in addition to receptor involvement. The physiological responses are provided along with integration into the unifying mechanistic theme of electron transfer (ET)-reactive oxygen species (ROS)-oxidative stress (OS). The multifaceted approach involving redox processes and cell signaling is unique in providing novel insight.     

The Contribution of TRPV4-Mediated Calcium Signaling to Calcium Homeostasis in Endothelial Cells

A large variety of cation transport systems are involved in the regulation of calcium homeostasis in endothelial cells. The focus of the present study is to determine the contribution of nonselective cation channels from the TRP (transient receptor potential) family to cellular calcium homeostasis of porcine aortic endothelial cells (PAEC). One member of the TRPV (vanniloid) subfamily, TRPV4, has previously been shown to be involved in cation transport induced by a large variety of stimulations including osmolarity, temperature, mechanical stress, and phosphorylation. Here, we demonstrate the existence of several TRP proteins, including TRPV4, in PAEC using RT-PCR. To test whether this channel is functional, we performed FURA-2 calcium measurements and whole-cell patch-clamp experiments. We observed the induction of large calcium signals following mechanical stress, altered extracellular temperature, and the selective TRPV4 activator 4-α -PDD. These effects were diminished in the presence of the TRPV4 inhibitor miconazole, suggesting the involvement of this channel in mediating endothelial calcium signals. The large amounts of transported calcium and the short signaling ways suggest a potentially important role of this channel in many physiological processes.