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PubMed1987

Calcium-dependent regulation of phospholipase A2 and its inhibitors, including tetracaine, for acetylcholine receptor cluster formation in mouse myotubes co-cultured with spinal cord explant.

Regulatory effects of phospholipase A2 (PLA2) on acetylcholine receptor (AChR) cluster formation were investigated in developing mouse myotubes co-cultured with spinal cord explant, using quinacrine, cortisone, tetracaine and related agents. AChR was visualized using the fluorescence-conjugated alpha-bungarotoxin. Peak fluorescence intensity and total fluorescence within the fluorescence stain were measured as indices of AChR cluster formation and AChR content, respectively. Both indices were gradually increased from day 9 to 13 in culture. PLA2 (0.2-1.0 micrograms/ml), melittin (10 micrograms/ml) and arachidonic acid (100 microM), added to the culture medium from the second day, clearly inhibited both indices at days 11 and 13, whereas the addition of phospholipase C (1 microgram/ml) inhibited peak fluorescence but did not affect total fluorescence. The co-existence of PLA2 with its inhibitors--quinacrine (3 microM), cortisone (0.01 microM) and tetracaine (30 microM)--significantly overcame the PLA2-induced inhibition of both indices. The elevation of calcium ion concentrations from 2.9 to 10 mM abolished the increase of both indices. Quinacrine (10 microM), cortisone (0.1 microM) and tetracaine (100 microM) alone similarly inhibited both fluorescence indices. The addition of EGTA (2 mM) from day 8 overcame tetracaine-induced inhibition but not quinacrine- or cortisone-induced inhibition. These results suggest that the formation of AChR clusters in developing myotubes is negatively controlled by endogenous PLA2 activity. This overcoming of PLA2-induced inhibition by tetracaine may be dependent on calcium ion mobilization, whereas that by quainacrine and cortisone may not.

Animals↗
PubMed1990

Intracellular signal transduction pathways in sponges.

Sponges are the lowest multicellular eukaryotic organisms. Due to the relatively low specialization, and concomitantly the high differentiation and dedifferentiation potency of their cells, the sponge cell system has proven to be a useful model to study the mechanism of cell-cell adhesion on molecular levels. Results of detailed biochemical and cell biological studies with the main cell adhesion molecules, the aggregation factor (AF) and the aggregation receptor, led to the formation of the modulation theory of cell adhesion. The events of cell adhesion are contigent on a multiplicity of precisely coordinated intracellular signal transduction pathways. Using the marine sponge Geodia cydonium we showed that during the initial phase of cell-cell contact the AF causes a rapid stimulation of the phosphatidylinositol pathway, resulting in an activation of protein kinase C and a subsequent phosphorylation of DNA topoisomerase II. As one consequence of these processes, the cells undergo a phase of high DNA synthesis. However, at later stages, the AF loses its mitogenic activity; this function is then taken over by the matrix lectin. During this switch, the lectin receptor associates in the plasma membrane with the ras oncogene product. The description of these processes is subject of this review article.

Animals↗
PubMed1990

The postsynaptic 43K protein clusters muscle nicotinic acetylcholine receptors in Xenopus oocytes.

Nicotinic acetylcholine receptors (AChRs) are localized at high concentrations in the postsynaptic membrane of the neuromuscular junction. A peripheral membrane protein of Mr 43,000 (43K protein) is closely associated with AChRs and has been proposed to anchor receptors at postsynaptic sites. We have used the Xenopus oocyte expression system to test the idea that the 43K protein clusters AChRs. Mouse muscle AChRs expressed in oocytes after injection of RNA encoding receptor subunits are uniformly distributed in the surface membrane. Coinjection of AChR RNA and RNA encoding the mouse muscle 43K protein causes AChRs to form clusters of 0.5-1.5 microns diameter. AChR clustering is not a consequence of increased receptor expression in the surface membrane or nonspecific clustering of all membrane proteins. The 43K protein is colocalized with AChRs in clusters when the two proteins are expressed together and forms clusters of similar size even in the absence of AChRs. These results provide direct evidence that the 43K protein causes clustering of AChRs and suggest that regulation of 43K protein clustering may be a key step in neuromuscular synaptogenesis.

Animals↗
PubMed1991

Induction of synaptic development in cultured muscle cells by basic fibroblast growth factor.

The role of basic fibroblast growth factor (bFGF) in signaling the development of the neuromuscular junction was examined. Beads coated with bFGF induced the formation of acetylcholine receptor (AChR) clusters in cultured Xenopus myotomal muscle cells. Tyrphostin, a tyrosine kinase inhibitor, abolished AChR clustering induced by bFGF beads, suggesting a role of tyrosine kinase activation in AChR clustering. Using specific antibodies, we demonstrated the presence of both bFGF and its receptor in the myotomal muscle in vivo during the period of neuromuscular connection. However, similar tissue from older animals with mature neuromuscular junctions showed an apparently truncated form of the bFGF receptor. These data suggest that bFGF may play a role in signaling synaptogenesis in skeletal muscle.

Animals↗
PubMed1992

RNA splicing regulates agrin-mediated acetylcholine receptor clustering activity on cultured myotubes.

Agrin is a component of the synaptic basal lamina that induces the clustering of acetylcholine receptors (AChRs) on muscle fibers. A region near the carboxyl terminus of the protein exists in four forms that are generated by alternative RNA splicing. All four alternatively spliced forms of agrin are active in inducing AChR clusters on rat primary and C2-derived muscle fibers. In contrast, only two forms of the protein, each containing an 8 amino acid insert, are capable of inducing clusters on myotubes of S27 cells, a C2 variant that has defective proteoglycans. These two forms are also most active in inducing clusters on chick myotubes. This pattern of differential activity suggests that RNA splicing of agrin transcripts and interactions with proteoglycans or other components of basal lamina have important roles in regulating the localization of neurotransmitter receptors at synaptic sites.

Agrin↗
PubMed1993

The ability of agrin to cluster AChRs depends on alternative splicing and on cell surface proteoglycans.

Agrin, which induces acetylcholine receptor (AChR) clustering at the developing neuromuscular synapse, occurs in multiple forms generated by alternative splicing. Some of these isoforms are specific to the nervous system; others are expressed in both neural and nonneural tissues, including muscle. We have compared the AChR clustering activity of agrin forms varying at each of the three identified splicing sites, denoted x, y, and z. Agrin isoforms were assayed by applying either transfected COS cells, with agrin bound to their surfaces, or soluble agrin to myotubes of the C2 muscle line, or of two variant lines having defective proteoglycans. Dramatic differences in activity were seen between z site isoforms and lesser differences between y site isoforms. The most active agrin forms contained splicing inserts of 4 amino acids at the y site and 8 amino acids at the z site. These forms are found exclusively in neural tissue. All forms were active on C2 myotubes in cell-attached assays, but muscle forms were less active than neural forms. AChR clustering activity of all agrin forms was decreased when assayed on the proteoglycan-deficient lines, suggesting that proteoglycans may help mediate the action of agrin. As neural agrin forms are more active than muscle forms, they are likely to play a primary role in synaptogenesis.

Agrin↗
PubMed1993

Cell-mediated cytotoxicity: contact and secreted factors.

The list of cells with cytotoxic potential now may include small resting T cells, but the exact nature of 'lethal hit delivery' by cytotoxic T lymphocytes remains elusive. Cell-mediated cytotoxicity by cytotoxic T lymphocytes is a complex, multistep process which seems likely to be mediated by several different pathways. Recent experimental evidence for the functioning of a novel cytotoxic mechanism through a target cell's surface receptor illustrates and emphasizes the necessity to study the interactions of cytotoxic T lymphocytes and target cells as a whole. Progress is evident in the description of molecular requirements for triggering cytotoxicity, cell-cell contacts and the regulation of the effector responses of cytotoxic T lymphocytes by extracellular, intracellular and granular proteins. Extracellular Ca(2+)-dependent secretion of perforin and protease(s) may explain several aspects of cellular cytotoxicity, whereas the apoptosis-mediating cell surface Fas protein is now implicated in Ca(2+)-independent cytotoxicity.

Adenosine Triphosphate↗
PubMed1995

Signal transduction through the conserved motifs of the high affinity IgE receptor Fc epsilon RI.

The high affinity receptor for IgE, Fc epsilon RI, possesses three ARAMs, one in the beta chain (ARAM-beta) and one in each member of the dimer of gamma chains (ARAM-gamma). These two types of ARAM endow the chains in which they are located with distinct properties. The ARAM-containing C-terminal tail of beta binds Lyn, a Src family tyrosine kinase which regulates the phosphorylation of beta, gamma and other substrates including Syk. The tyrosine phosphorylated ARAM-containing C-terminal tail of gamma binds Syk which, when activated, controls later signals such as the rise in intracellular calcium. Therefore, the two ARAM-containing chains of Fc epsilon RI cooperate to realize the full signaling capacity of the receptor.

Amino Acid Sequence↗
PubMed1995

Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells.

OX40 is a member of the TNF/NGF-receptor family expressed on activated T cells, whose ligand is found on activated T and B cells. In the present study, we show that cross-linking of OX40L on CD40L-stimulated B cells, alpha IgD dextran-stimulated B cells, or both results in a significantly enhanced proliferative response with no change in the cell survival rate. Furthermore, OX40 stimulation increases immunoglobulin heavy chain mRNA levels and immunoglobulin secretion, which could not be blocked by anti-cytokine antibodies. In additional molecular studies, we show that OX40L cross-linking results in the down-regulation of the transcription factor BSAP. This, in turn, leads to a change in the in vivo binding pattern of the immunoglobulin heavy chain gene 3' alpha enhancer, suggesting its activation. This effect may thus be one mechanism for OX40-induced increase in immunoglobulin secretion. In conclusion, our data suggest that the OX40-OX40L interaction is a novel pathway in T cell-dependent B cell proliferation and differentiation.

Animals↗
PubMed1995

TCR alpha-CD3 delta epsilon association is the initial step in alpha beta dimer formation in murine T cells and is limiting in immature CD4+ CD8+ thymocytes.

The present study has examined the molecular events leading to formation of alpha beta dimers in normal murine thymocytes and mature T cells. We demonstrate that TCR assembly proceeds by initial association of TCR alpha with CD3 delta epsilon proteins and by association of TCR beta with CD3 gamma epsilon proteins to form alpha delta epsilon and beta gamma epsilon trimers; these trimers then associate to form alpha delta epsilon-beta gamma epsilon complexes, within which alpha-beta disulfide bond formation occurs. We also show that TCR-associated protein (TRAP) associates uniquely with CD3 gamma epsilon pairs and that formation of beta gamma epsilon trimers occurs subsequent to TRAP dissociation. Importantly, we document that the assembly step that is quantitatively limiting in CD4+ CD8+ thymocytes is the initial association of TCR alpha with CD3 delta epsilon chains, which appears necessary to protect nascent TCR alpha proteins from accelerated degradation within the ER of immature thymocytes.

Animals↗
PubMed1995

TCR-associated zeta-Fc epsilon RI gamma heterodimers on CD4-CD8- NK1.1+ T cells selected by specific class I MHC antigen.

The origin of autoreactive CD4-CD8- T cells is largely unknown. In TCR transgenic (Tg) mice expressing the cognate class I MHC antigen, CD4-CD8- T cells differed depending on characteristics of Tg-TCR/antigen interaction. Tg-TCR/CD3lo CD4-CD8- T cells expressing the NK1.1 marker were observed only for a Tg-TCR whose stimulation by antigen was independent of CD8. Unlike normal T cells, which have essentially TCR-associated zeta homodimers, these cells had a high proportion of TCR-associated zeta-Fc epsilon RI gamma heterodimers. They were also characterized by an unusually high content of Fc epsilon RI gamma mRNA and low content of mRNA encoding CD3 epsilon, CD3 gamma, CD3 delta, and zeta. Based on their phenotype and selection requirements, it is proposed that CD4-CD8- thymic precursor cells can be driven along the CD4-CD8-NK1.1+ pathway following coreceptor-independent TCR signaling at an intrathymic stage when Fc epsilon RI gamma and CD3 components are coexpressed.

Animals↗
PubMed2004

Combining baseline clinical descriptors and real-time response to therapy: the incremental prognostic value of continuous ST-segment monitoring in acute myocardial infarction.

BACKGROUND: Clinical descriptors and ST-segment recovery variables hold prognostic information for clinical outcome after thrombolysis for acute myocardial infarction (MI). We sought to define the incremental prognostic value of continuous 12-lead ST-segment monitoring variables to clinical risk descriptors identified by the Global Utilization of Streptokinase and TPA (alteplase) for Occluded Coronary Arteries (GUSTO-I) trial 30-day mortality analysis. METHODS: Of 1,777 patients enrolled in continuous ST-segment substudies from the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI-9), GUSTO-I, Duke University Clinical Cardiology Study (DUCCS-II), Integrilin to manage Platelet Aggregation to Combat Thrombus in Acute Myocardial Infarction (IMPACT-AMI), Promotion of Reperfusion by Inhibition of Thrombin During Myocardial Infarction Evolution (PRIME), and Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) trials, 825 patients qualified for assessment of time to recovery. ST recovery variables analyzed were time to stable ST-recovery and late ST elevation. Patients who were at low clinical risk (n = 261) had no high-risk descriptors, and patients at high clinical risk (n = 564) had at least 1 of these high-risk descriptors: age >or=70 years, systolic blood pressure or=90 beats/min, anterior MI, or previous MI. High (n = 90), moderate (n = 318), and low (n =417) ST-risk groups were defined by the presence of both slow ST recovery and late ST elevation, one or the other, or neither, respectively. End points analyzed were inhospital death and combined death, reinfarction, or congestive heart failure. RESULTS: There was a trend toward increased mortality rate in the high-clinical/high-ST-risk group. For the composite end point, ST subgrouping resulted in significant event stratification in both patients at low and high clinical risk. In multivariable analysis, age and heart rate were independent predictors of both mortality and the composite end point. Late ST elevation added incremental prognostic information. CONCLUSION: Age, heart rate, and late ST elevation are powerful, independent predictors of adverse clinical outcome. Continuous monitoring allows noninvasive assessment of the response to therapy. Consequently, this technique will enhance the potential to risk-stratify individual patients in a real-time setting.

Aged↗
PubMed2006

Low affinity binding of the classical D1 antagonist SCH23390 in rodent brain: potential interaction with A2A and D2-like receptors.

Whereas structurally dissimilar D(1) antagonists competing for [(3)H]-SCH23390 binding recognize primarily one site in striatum, two distinct affinity states are observed in both amygdala and hippocampus. The binding profile of SCH23390 is similar in both of these regions, with the high affinity site (K(D) approximately 0.4 nM) consistent with D(1)/D(5) receptors. The appearance of the low affinity site (K(D) approximately 300 nM) is dependent upon the absence of MgCl(2), but independent of D(1) expression (i.e., still present in D(1) knockout mice). Although the density of high affinity state receptor is lower in hippocampus or amygdala of D(1) knockout mice, some residual binding remains, consistent with the known expression of D(5) receptors in these regions. Remarkably, in hippocampus, the affinity of the low affinity site is shifted rightward in the presence of the D(2) antagonist domperidone and is largely absent in the hippocampus of D(2) knockout animals. Additionally, this site is also shifted rightward in the presence of the A(2A) ligands SCH58261, CSC, or NECA, or in the absence of A(2A) receptors. The affinity of SCH23390 for this low affinity site is greater than seen for SCH23390 binding to D(2) receptors in heterologous expression systems, consistent with the hypothesis that both D(2) and A(2A) receptors are involved in the low affinity binding site. Therefore, we suggest that the heteromerization of D(2) and A(2A) receptors reported previously in vitro also may occur in the brain of both rats and mice.

Adenosine↗
PubMed2004

Changes on the properties of glycine receptors during neuronal development.

Glycine receptors (GlyRs) play a major role in the excitability of spinal cord and brain stem neurons. During development, several properties of these receptors undergo significant changes resulting in major modifications of their physiological functions. For example, the receptor structure switches from a monomeric alpha or heteromeric alpha 2 beta in immature neurons to an alpha 1 beta receptor type in mature neurons. Together with these changes in receptor subunits, the postsynaptic cluster size increases with development. Parallel to these modifications, the apparent receptor affinity to glycine and strychnine, as well as that of Zn(2+) and ethanol increases with time. The mature receptor is characterized by a slow desensitizing current and high sensitivity to modulation by protein kinase C. Also, the high level of glycinergic transmission in immature spinal neurons modulates neuronal excitability causing membrane depolarization and changes in intracellular calcium. Due to these properties, chronic inhibition of glycinergic transmission affects neurite outgrowth and produces changes in the level of synaptic transmission induced by GABA(A) and AMPA receptors. Finally, the high level of plasticity found in immature GlyRs is likely associated to changes in cytoskeleton dynamics.

Animals↗
PubMed2005

EGF receptor inhibition: attacks on multiple fronts.

The epidermal growth factor receptor (EGFR) drives tumor growth in a subset of human epithelial carcinomas. A crystallographic study by Li et al. in this issue of Cancer Cell provides the molecular basis for inhibition of EGFR by cetuximab (Erbitux), a monoclonal antibody that has been approved by the Food and Drug Administration as a therapeutic for advanced-stage colorectal cancers. Cetuximab targets one of the ligand binding domains of EGFR, thus preventing ligand activation of the receptor.

Antibodies, Monoclonal↗
PubMed2004

Independent regulation of synaptic size and activity by the anaphase-promoting complex.

Neuronal plasticity relies on tightly regulated control of protein levels at synapses. One mechanism to control protein abundance is the ubiquitin-proteasome degradation system. Recent studies have implicated ubiquitin-mediated protein degradation in synaptic development, function, and plasticity, but little is known about the regulatory mechanisms controlling ubiquitylation in neurons. In contrast, ubiquitylation has long been studied as a central regulator of the eukaryotic cell cycle. A critical mediator of cell-cycle transitions, the anaphase-promoting complex/cyclosome (APC/C), is an E3 ubiquitin ligase. Although the APC/C has been detected in several differentiated cell types, a functional role for the complex in postmitotic cells has been elusive. We describe a novel postmitotic role for the APC/C at Drosophila neuromuscular synapses: independent regulation of synaptic growth and synaptic transmission. In neurons, the APC/C controls synaptic size via a downstream effector Liprin-alpha; in muscles, the APC/C regulates synaptic transmission, controlling the concentration of a postsynaptic glutamate receptor.

Anaphase-Promoting Complex-Cyclosome↗
PubMed2005

Interaction with vesicle luminal protachykinin regulates surface expression of delta-opioid receptors and opioid analgesia.

Opioid and tachykinin systems are involved in modulation of pain transmission in the spinal cord. Regulation of surface opioid receptors on nociceptive afferents is critical for opioid analgesia. Plasma-membrane insertion of delta-opioid receptors (DORs) is induced by stimulus-triggered exocytosis of DOR-containing large dense-core vesicles (LDCVs), but how DORs become sorted into the regulated secretory pathway is unknown. Here we report that direct interaction between protachykinin and DOR is responsible for sorting of DORs into LDCVs, allowing stimulus-induced surface insertion of DORs and DOR-mediated spinal analgesia. This interaction is mediated by the substance P domain of protachykinin and the third luminal domain of DOR. Furthermore, deletion of the preprotachykinin A gene reduced stimulus-induced surface insertion of DORs and abolished DOR-mediated spinal analgesia and morphine tolerance. Thus, protachykinin is essential for modulation of the sensitivity of nociceptive afferents to opioids, and the opioid and tachykinin systems are directly linked by protachykinin/DOR interaction.

Afferent Pathways↗
PubMed2004

Transient overexpression of kappa and mu opioid receptors using recombinant adenovirus vectors.

In order to study the trafficking and signal transduction mechanisms of the multiple opioid receptors, these receptors are expressed either transiently or stably in cell lines. Often, it is difficult to express receptors at a sufficiently high density to obtain reproducible results. To achieve a high density of receptors, replication-defective adenovirus (rAd5) vectors encoding the mu (MOR) and kappa (KOR) opioid receptors, both in their native form and as fusion proteins bearing the green fluorescent protein (GFP) at their C-terminus, were constructed. These vectors efficiently and reproducibly infected Chinese hamster ovary (CHO) cells that stably express the human coxsackie-adenovirus receptor (hCAR), with up to 90% of cells becoming infected at a low multiplicity of infection (MOI). Saturation receptor binding studies using mu- and kappa-selective agonists, [3H][D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) and [3H](5alpha7alpha,8beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)benzeneacetamide (U69,593), respectively, and a nonselective antagonist, [3H]diprenorphine, revealed that rAd5-transduced cells expressed MOR and KOR for at least 3 days, at levels which exceeded those present on widely-used CHO sublines that stably express MOR or KOR. Expression levels were highest for the vectors encoding native MOR or KOR, and slightly reduced for the GFP fusion proteins. These findings demonstrate the feasibility of using rAd5 vectors to express opioid receptors at high densities, which may facilitate opioid receptor studies.

Adenoviridae↗