Extracellular signals, transcriptional responses and cellular specificity

The expression of a relatively small set of common primary response genes is frequently induced, in a variety of cellular responses, by growth factors, protein hormones and neurotransmitters. The characterization of these genes and their products may provide clues to the mechanisms by which ligand- and cell-specific responses may be generated.     

Retrograde signaling and plant stress: plastid signals initiate cellular stress responses

Retrograde signaling coordinates the expression of nuclear genes encoding organellar proteins with the metabolic and developmental state of the organelle. These plastid signals are essential not only for coordinating photosynthetic gene expression in both the nucleus and in the chloroplasts but also for mediating plant stress responses. The chloroplasts therefore act as sensors of environmental changes and complex networks of plastid signals coordinate cellular activities and assist the cell during plant stress responses. Recent work suggests that information from both cytosolic-signaling and plastid-signaling networks must be integrated for the plant cell to respond optimally to environmental stress.     

Adaptive responses and cellular behaviour of biphenyl-degrading bacteria toward polychlorinated biphenyls

Polychlorinated biphenyls (PCBs) are one of the most widely distributed classes of chlorinated chemicals in the environment. For cleanup of large areas of PCB-contaminated environments, bioremediation seems to be a promising approach. However, the multitude of PCB congeners, their low bioavailability and high toxicity are important factors that affect the cleanup progression. Elucidating how the PCB-degrading microorganisms involved in the process adapt to and deal with the stressing conditions caused by this class of compounds may help to improve the bioremediation process. Also specific physiological characteristics of biphenyl-utilizing bacteria involved in the degradation of PCBs may enhance their availability to these compounds and therefore contribute to a better microbial mineralization. This review will focus in the stress responses caused in aerobic biphenyl-utilizing bacteria by PCBs and its metabolic intermediates and will also analyze bacterial properties such as motility and chemotaxis, adherence to solid surfaces, biosurfactant production and biofilm development, all properties found to enhance bacteria-pollutant interaction.     

A dose-response model for teratological experiments involving quantal responses

This paper introduces a dose-response model for teratological quantal response data where the probability of response for an offspring from a female at a given dose varies with the litter size. The maximum likelihood estimators for the parameters of the model are given as the solution of a nonlinear iterative algorithm. Two methods of low-dose extrapolation are presented, one based on the litter size distribution and the other a conservative method. The resulting procedures are then applied to a teratological data set from the literature.     

Metal-induced toxicity, carcinogenesis, mechanisms and cellular responses

A wide variety of metals have been reported to act as mutagenic and carcinogenic agents in both human and animal studies. The underlying mechanisms are being extensively investigated. Recently, a new sub-discipline of molecular carcinogenesis has surfaced and new techniques and instruments are being developed which allow exploration of the complex biological relationships and signaling pathways involved in response to metal exposure at the molecular level. The 2nd Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenesis was held at NIOSH in Morgantown, West Virginia, Sept. 8-11, 2002. One hundred thirty scientist from sixteen countries presented their novel findings and investigations of metal-induced carcinogenesis. The conference focused on state-of-the-art research and developments in metal toxicity and carcinogenesis. Emphasis was placed on delineating molecular mechanisms involved in free radical effects, cellular uptake, signaling pathways/interaction, dose response, biomarkers, and resistance mechanisms. This article reviews some of the novel information presented at the conference and discusses future avenues of research in this field.     

myo-inositol metabolites as cellular signals

The discovery of the second-messenger functions of inositol 1,4,5-trisphosphate and diacylglycerol, the products of hormone-stimulated inositol phospholipid hydrolysis, marked a turning point in studies of hormone function. This review focuses on the myo-inositol moiety which is involved in an increasingly complex network of metabolic interconversions, myo-Inositol metabolites identified in eukaryotic cells include at least six glycerophospholipid isomers and some 25 distinct inositol phosphates which differ in the number and distribution of phosphate groups around the inositol ring. This apparent complexity can be simplified by assigning groups of myo-inositol metabolites to distinct functional compartments. For example, the phosphatidylinositol 4-kinase pathway functions to generate inositol phospholipids that are substrates for hormone-sensitive forms of inositol-phospholipid phospholipase C, whilst the newly discovered phosphatidylinositol 3-kinase pathway generates lipids that are resistant to such enzymes and may function directly as novel mitogenic signals. Inositol phosphate metabolism functions to terminate the second-messenger activity of inositol 1,4,5-trisphosphate, to recycle the latter's myo-inositol moiety and, perhaps, to generate additional signal molecules such as inositol 1,3,4,5-tetrakisphosphate, inositol pentakisphosphate and inositol hexakisphosphate. In addition to providing a more complete picture of the pathways of myo-inositol metabolism, recent studies have made rapid progress in understanding the molecular basis underlying hormonal stimulation of inositol-phospholipid-specific phospholipase C and inositol 1,4,5-trisphosphate-mediated Ca2+ mobilisation.     

Biphasic responses to acetylcholine in mammalian reticulospinal neurons

Acetylcholine (ACh) responses were elicited by ionophoresis from neurons, located in the medial pontine reticular formation, which were antidromically identified as having axons projecting in the reticulospinal tracts. Most neurons were silent at rest and could be caused to discharge at a regular, slow rate by a constant application of glutamate. ACh altered this slow rate of firing in 28 of 29 cells but showed three different patterns of effect: approximately one-third were excited, one-third were inhibited, and one-third showed biphasic inhibition-excitation. The ACh responses were not sensitive to atropine. These observations suggest that reticulospinal neurons have ACh receptors mediating both inhibition and excitation, perhaps located on different portions of the same neuron.     

Sphingomyelin and derivatives as cellular signals.

This comprehensive review was necessitated by recent observations suggesting that sphingomyelin and derivatives may serve second messenger functions. It has attempted to remain true to the theme of cellular signalling. Hence, it has focussed on the lipids involved primarily with respect to their metabolism and properties in mammalian systems. The enzymology involved has been emphasized. An attempt was made to define directions in which signals may be flowing. However, the evidence presented to date is insufficient to conclusively designate the mechanisms of stimulated lipid metabolism. Hence, the proposed pathways must be viewed as preliminary. Further, the biologic functions of these lipids is for the most part uncertain. Thus, it is difficult to presently integrate this sphingomyelin pathway into the greater realm of cell biology. Nevertheless, the present evidence appears to suggest that a sphingomyelin pathway is likely to possess important bioregulatory functions. Hopefully, interest in this novel pathway will grow and allow a more complete understanding of the roles of these sphingolipids in physiology and pathology.     

Regulation of cellular signals by G-proteins

Extracellular signals are transduced across the cell by the cell surface receptors, with the aid of G-proteins, which act at a critical point of signal transduction and cellular regulation. Structurally, G-proteins are heterotrimeric consisting α, β and γ subunits but in functionally active state they dissociate into α subunit coupled to GTP and as βγ dimer. G-proteins can be broadly divided into two classes based on their sensitivity to pertussis toxin and cholera toxin. Existence of various forms of each of the subunit allows molecular diversity in the subunit species of G-proteins. These subunits interact with a wide range of receptors and effectors, facilitated by post translational modification of their subunits. Different types of G-proteins mediate several signalling events in different parts of the body. This review summarizes the features of (i) structural and functional heterogenity among different subunits of G-proteins, (ii) interaction of G-proteins and their subunits with effectors with specific cases of G-protein mediated signalling in olfaction, phototransduction in the retina, ras andras related transduction and (iii) disease conditions associated with malfunctioning of G-proteins.     

Field-effect devices for detecting cellular signals

The integration of living cells together with silicon field-effect devices challenges a new generation of biosensors and bioelectronic devices. Cells are representing highly organised complex systems, optimised by millions of years of evolution and offering a broad spectrum of bioanalytical receptor “tools” such as enzymes, nucleic acids proteins, etc. Their combination with semiconductor-based electronic chips allows the construction of functional hybrid systems with unique functional and electronic properties for both fundamental studies and biosensoric applications. This review article summarises recent advances and trends in research and development of cell/transistor hybrids (cell-based field-effect transistors) as well as light-addressable potentiometric sensors.     

Generic signal-specific responses: cytokinin and context-dependent cellular responses

The phytohormone cytokinin triggers numerous and diverse responses during the plant life cycle via a two-component phosphorelay signalling system. Each step of the signalling cascade is supported by a gene family comprising several members. While functional redundancy is observed among family members, additional gene-specific functions encoded by cis-regulatory and coding sequence of individual family members have been described and contribute to specificity in signalling output. In addition, the cellular context of the signal-receiving cell affects the response triggered. Recent studies in Arabidopsis have demonstrated how expression of cytokinin signalling components predefines a spatiotemporal map of signalling sensitivity, which causes local signal amplification and attenuation. In summary, the specific interpretation of cytokinin signalling is affected by an orchestrated interplay of signalling genes and cellular context.     

Initiating cellular stress responses

The phosphoinositide 3-kinase related kinases (PIKKs) mediate responses to diverse stresses, including DNA double-strand breaks (DSBs), abnormal replication fork progression, the recognition of premature termination codons in mRNAs, and inadequate nutrient availability. Rigorous control of these kinases limits cellular damage and promotes cell viability in the presence of stress. Control mechanisms include the localization of PIKKs into multiprotein complexes at the sites of damage and mediation of protein-protein contacts such that substrates are allowed access to the PIKK catalytic domains.     

Amplification of calcium signals at dendritic spines provides a method for CNS quantal analysis

It has been proposed that the small volume of a dendritic spine can amplify Ca2+ signals during synaptic transmission. Accordingly, we have performed calculations to determine whether the activation of N-methyl-D-aspartate (NMDA) type glutamate receptors during synaptic transmission results in significant elevation in intracellular Ca2+ levels, permitting optical detection of synaptic signals within a single spine. Simple calculations suggest that the opening of even a single NMDA receptor would result in the influx of approximately 310 000 Ca2+ ions into the small volume of a spine, producing changes in Ca2+ levels that are readily detectable using high affinity Ca2+ indicators such as fura-2 or fluo-3. Using fluorescent Ca2+ indicators, we have imaged local Ca2+ transients mediated by NMDA receptors in spines and dendritic shafts attributed to spontaneous miniature synaptic activity. Detailed analysis of these quantal events suggests that the current triggering these transients is attributed to the activation of <10 NMDA receptors. The frequency of these miniature synaptic Ca2+ transients is not randomly distributed across synapses, as some synapses can display a >10-fold higher frequency of transients than others. As expected for events mediated by NMDA receptors, miniature synaptic Ca2+ transients were suppressed by extracellular Mg2+ at negative membrane potentials; however, the Mg2+ block could be removed by depolarization.     

Integration of cellular signals in chattering environments

Cells are constantly exposed to fluctuating environmental conditions. External signals are sensed, processed and integrated by cellular signal transduction networks, which translate input signals into specific cellular responses by means of biochemical reactions. These networks have a complex nature, and we are still far from having a complete characterization of the process through which they integrate information, specially given the noisy environment in which that information is embedded. Guided by the many instances of constructive influences of noise that have been reported in the physical sciences in the last decades, here we explore how multiple signals are integrated in an eukaryotic cell in the presence of background noise, or chatter. To that end, we use a Boolean model of a typical human signal transduction network. Despite its complexity, we find that the network is able to display simple patterns of signal integration. Furthermore, our computational analysis shows that these integration patterns depend on the levels of fluctuating background activity carried by other cell inputs. Taken together, our results indicate that signal integration is sensitive to environmental fluctuations, and that this background noise effectively determines the information integration capabilities of the cell.     

Action spectrum and quantal thresholds of retinomotor responses in the brook trout,Salvelinus fontinalis (Mitchill)

Summary The radiant energy per unit area required to trigger retinomotor responses was determined for eight wavelengths. The curve's maximum at 520 nanometres corresponds to two microwatts per steradian per square metre. The threshold requires the absorption of 7000 quanta per second per square degree of the field by the scotopic pigment.

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Zusammenfassung Die je Einheitsbereich erforderliche Strahlungsenergie für die Auslösung der retinomotorischen Reaktion wurde für acht Wellenlängen gemessen. Das Maximum der Kurve (520 Nanometer) entspricht zwei Mikrowatt pro Steradian pro Quadratmeter. Im Bereiche des Schwellenwertes ist eine Absorption des Feldes durch das skotopische Pigment von 7000 Quanten pro Sekunde, pro Quadratgrad benötigt.

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Supported by a grant from the National Research Council of Canada.     

Biphasic activation of cytosolic free calcium and LH responses by gonadotropin-releasing hormone

Gonadotropin-releasing hormone (GnRH) stimulates rapid peak increases in [Ca2+]i and LH release, followed by lower but sustained elevations of both [Ca2+]i and hormone secretion. Omission of extracellular Ca2+ only slightly decreased the peak of [Ca2+]i, but reduced the peak LH response by 40% and prevented the prolonged increases in [Ca2+]i and LH release. Dihydropyridine calcium antagonists did not affect the peak [Ca2+]i and LH responses, but reduced the sustained increases by up to 50%. Whereas GnRH-induced mobilization of intracellular calcium initiates the LH peak, and Ca2+ entry through dihydropyridine-insensitive channels contributes to the peak and plateau phases of LH release, dihydropyridine-sensitive L-type Ca2+ channels participate only in the sustained phase of gonadotropin secretion.