Pre & postsynaptic tuning of action potential timing by spontaneous GABAergic activity

Frequency and timing of action potential discharge are key elements for coding and transfer of information between neurons. The nature and location of the synaptic contacts, the biophysical parameters of the receptor-operated channels and their kinetics of activation are major determinants of the firing behaviour of each individual neuron. Ultimately the intrinsic excitability of each neuron determines the input-output function. Here we evaluate the influence of spontaneous GABAergic synaptic activity on the timing of action potentials in Layer 2/3 pyramidal neurones in acute brain slices from the somatosensory cortex of young rats. Somatic dynamic current injection to mimic synaptic input events was employed, together with a simple computational model that reproduce subthreshold membrane properties. Besides the well-documented control of neuronal excitability, spontaneous background GABAergic activity has a major detrimental effect on spike timing. In fact, GABA(A) receptors tune the relationship between the excitability and fidelity of pyramidal neurons via a postsynaptic (the reversal potential for GABA(A) activity) and a presynaptic (the frequency of spontaneous activity) mechanism. GABAergic activity can decrease or increase the excitability of pyramidal neurones, depending on the difference between the reversal potential for GABA(A) receptors and the threshold for action potential. In contrast, spike time jitter can only be increased proportionally to the difference between these two membrane potentials. Changes in excitability by background GABAergic activity can therefore only be associated with deterioration of the reliability of spike timing.     

Fine tuning of TCR signaling by CD5

Current data indicate that CD5 functions as an inhibitor of TCR signal transduction. Consistent with this role, thymocyte selection in TCR transgenic/CD5(-/-) mice is altered in a manner suggestive of enhanced TCR signaling. However, the impact of CD5 deletion on thymocyte selection varies depending on the transgenic TCR analyzed, ranging from a slight to a marked shift from positive toward negative selection. An explanation for the variable effect of CD5 on selection is suggested by the observation that CD5 surface expression is regulated by TCR signal intensity during development and CD5 surface levels on mature thymocytes and T cells parallel the avidity of the positively selecting TCR/MHC/ligand interaction. In this study, we generated mice that overexpress CD5 during thymocyte development (CD5-tg), and then examined the effect of CD5 overexpression or CD5 deletion (CD5(-/-)) on selection of thymocytes that express the same TCR transgenes. The results demonstrate that the effect on thymocyte selection of altering CD5 expression depends on the avidity of the selecting interaction and, consequently, the level of basal (endogenous) CD5 surface expression. Substitution of endogenous CD5 with a transgene encoding a truncated form of the protein failed to rescue the CD5(-/-) phenotype, demonstrating that the cytoplasmic domain of CD5 is required for its inhibitory function. Together, these results indicate that inducible regulation of CD5 surface expression during thymocyte selection functions to fine tune the TCR signaling response.     

Cell signaling pathways engaged by KSHV

Kaposi's sarcoma herpesvirus (KSHV) is the eighth human herpesvirus discovered in 1994 from Kaposi's sarcoma lesion of an AIDS patient. The strong molecular and epidemiological links associating KSHV with Kaposi's sarcoma and certain lymphoproliferative disorders indicate that KSHV is required for the development of these malignancies. Although KSHV is equipped to manipulate and deregulate several cellular signaling pathways, it is not yet understood how this leads to cell transformation. Profound understanding of the interplay of viral and cellular factors in KSHV-infected cells will provide valuable information on the mechanisms of viral tumorigenesis and enable development of efficient targeted therapies for virus-induced cancers. This review focuses on the cellular signaling pathways that KSHV gene products impinge on and discusses their putative contribution to tumorigenesis.     

Nociceptive tuning by stem cell factor/c-Kit signaling

The molecular mechanisms regulating the sensitivity of sensory circuits to environmental stimuli are poorly understood. We demonstrate here a central role for stem cell factor (SCF) and its receptor, c-Kit, in tuning the responsiveness of sensory neurons to natural stimuli. Mice lacking SCF/c-Kit signaling displayed profound thermal hypoalgesia, attributable to a marked elevation in the thermal threshold and reduction in spiking rate of heat-sensitive nociceptors. Acute activation of c-Kit by its ligand, SCF, resulted in a reduced thermal threshold and potentiation of heat-activated currents in isolated small-diameter neurons and thermal hyperalgesia in mice. SCF-induced thermal hyperalgesia required the TRP family cation channel TRPV1. Lack of c-Kit signaling during development resulted in hypersensitivity of discrete mechanoreceptive neuronal subtypes. Thus, c-Kit can now be grouped with a small family of receptor tyrosine kinases, including c-Ret and TrkA, that control the transduction properties of sensory neurons.     

Targeting oncogenic signaling pathways by exploiting nanotechnology

Two scientific areas have recently emerged that can revolutionize cancer chemotherapy. First, an understanding of the different cellular signaling pathways implicated in the development and progression of cancer resulting in poor prognosis and drug resistance, have identified potential drug targets. Inhibitors of signal transduction pathways are currently in the clinics. Secondly, nanotechnology has emerged as an exciting multidisciplinary field promising to provide breakthrough solutions to the problems of optimizing the efficacy or therapeutic index of anticancer agents. The promise of nanotechnology lies in the ability to engineer customizable nanoscale constructs that can be loaded with one or more payloads such as chemotherapeutics, targeting units, imaging and diagnostic agents. This review addresses the potential integration of these two approaches to engineer nanoparticles that can target various signal transduction pathways in cancer.     

Angiotensin II signaling pathways mediated by tyrosine kinases

Angiotensin II (AngII) plays a critical role in control of cardiovascular and renal homeostasis. In addition to its physiological action as a vasoconstrictor, growing evidence supports the notion that AngII contributes to cardiovascular diseases such as hypertension, atherosclerosis, and heart failure. The physiological and pathological actions of AngII in adults are mediated largely via the AngII type 1 receptor (AT1R), a heterotrimeric G-protein-coupled receptor (GPCR). Besides coupling with heterotrimeric G proteins to activate phospholipase C-beta (PLC-beta), AT1R also activates receptor tyrosine kinases (PDGF-R, EGF-R and IGF-R) and non-receptor tyrosine kinases (Src, Fyn, Yes, proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK) and JAK2). These tyrosine kinases play critical roles in AngII-stimulated cell signal events.     

Uracil-induced signaling pathways for DUOX-dependent gut immunity

ABSTRACT

Intestinal dual oxidase (DUOX) activation is the first line of host defense against enteric infection in Drosophila. DUOX enzymatic activity is mainly controlled by phospholipase C-β (PLCβ)-dependent calcium mobilization, whereas DUOX gene expression is mainly controlled by the MEKK1-p38 mitogen-activated protein kinase pathway. Furthermore, bacterial-derived uracil molecules act as ligands for DUOX activation. However, our current understanding of uracil-induced signal transduction pathways remain incomplete. We have recently found that uracil stimulates Hedgehog signaling, which in turn upregulates cadherin99C (Cad99C) expression in enterocytes. Cad99C molecules, along with PLCβ and protein kinase C, induce the formation of signaling endosomes that facilitate intracellular calcium mobilization for DUOX activity. These observations illustrate the complexity of signaling cascades in uracil-induced signaling pathways. Here, we further demonstrated the role of lipid raft formation and calmodulin-dependent protein kinase-II on endosome formation and calcium mobilization, respectively. Moreover, we will provide a brief discussion on two different models for uracil recognition and uracil-induced DUOX activation in Drosophila enterocytes.     

Inhibition of growth factor signaling pathways by lovastatin

Human fibroblasts treated with the antihypercholesterolaemic drug, lovastatin, displayed a diminished signaling response to epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). Supplementing the culture medium with mevalonic acid restored the signaling response. Not all growth factor signaling pathways were impaired, however, as platelet-derived growth factor (PDGF-BB) and basic fibroblast growth factor (bFGF) responses were refractory to lovastatin treatment. These results suggest the involvement of product(s) of mevalonate metabolism (e.g., prenylated proteins such as p21ras or G proteins) in the signal transduction of EGF, insulin and IGF-I. The inhibition of cell growth by lovastatin may be caused by the inability of the cell to enter the S phase of the cell cycle due to obstruction of the signaling of progression factors.     

Cell signaling pathways altered by natural chemopreventive agents

Epidemiological studies have indicated a significant difference in the incidence of cancers among ethnic groups, who have different lifestyles and have been exposed to different environmental factors. It has been estimated that more than two-thirds of human cancers, which are contributed by mutations in multiple genes, could be prevented by modification of lifestyle including dietary modification. The consumption of fruits, soybean and vegetables has been associated with reduced risk of several types of cancers. The in vitro and in vivo studies have demonstrated that some dietary components such as isoflavones, indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), curcumin, (-)-epigallocatechin-3-gallate (EGCG), apigenin, etc., have shown inhibitory effects on human and animal cancers, suggesting that they may serve as chemopreventive agents. Experimental studies have also revealed that these components regulate the molecules in the cell signal transduction pathways including NF-kappaB, Akt, MAPK, p53, AR, and ER pathways. By modulating cell signaling pathways, these components, among other mechanisms, activate cell death signals and induce apoptosis in precancerous or cancer cells, resulting in the inhibition of cancer development and/or progression. This article reviews current studies regarding the effects of natural chemopreventive agents on cancer-related cell signaling pathways and provides comprehensive knowledge of the biological and molecular roles of chemopreventive agents in cancer cells.