The endoplasmic reticulum: a multifunctional signaling organelle

There is substantial evidence that sphingosine 1-phosphate (S1P) is involved in cancer. S1P regulates processes such as inflammation, which can drive tumorigenesis; neovascularization, which provides cancer cells with nutrients and oxygen; and cell growth and survival. This occurs at multiple levels and involves S1P receptors, sphingosine kinases, S1P phosphatases and S1P lyase. This Review summarizes current research findings and examines the potential for new therapeutics designed to alter S1P signalling and function in cancer.

/pdf/sphingosine-1-phosphate-and-cancer-3d2i2rmbom.pdf

Sphingosine 1-phosphate and cancer.

Background: Salmonid fishes are among the most widely studied model fish species but reports on systematic evaluation of reference genes in qRT-PCR studies is lacking. Results: The stability of six potential reference genes was examined in eight tissues of Atlantic salmon (Salmo salar), to determine the most suitable genes to be used in quantitative real-time RTPCR analyses. The relative transcription levels of genes encoding 18S rRNA, S20 ribosomal protein, β-actin, glyceraldehyde-3P-dehydrogenase (GAPDH), and two paralog genes encoding elongation factor 1A (EF1AA and EF1AB) were quantified in gills, liver, head kidney, spleen, thymus, brain, muscle, and posterior intestine in six untreated adult fish, in addition to a group of individuals that went through smoltification. Based on calculations performed with the geNorm VBA applet, which determines the most stable genes from a set of tested genes in a given cDNA sample, the ranking of the examined genes in adult Atlantic salmon was EF1AB>EF1AA>β-actin>18S rRNA>S20>GAPDH. When the same calculations were done on a total of 24 individuals from four stages in the smoltification process (presmolt, smolt, smoltified seawater and desmoltified freshwater), the gene ranking was EF1A B >EF1A A >S20>β-actin>18S rRNA>GAPDH. Conclusion: Overall, this work suggests that the EF1AA and EF1AB genes can be useful as reference genes in qRT-PCR examination of gene expression in the Atlantic salmon.

/pdf/evaluation-of-potential-reference-genes-in-real-time-rt-pcr-1gjw83w7wc.pdf

Evaluation of potential reference genes in real-time RT-PCR studies of Atlantic salmon

▪ Abstract In the gastrointestinal tract, phasic contractions are caused by electrical activity termed slow waves. Slow waves are generated and actively propagated by interstitial cells of Cajal (ICC). The initiation of pacemaker activity in the ICC is caused by release of Ca2+ from inositol 1,4,5-trisphosphate (IP3) receptor–operated stores, uptake of Ca2+ into mitochondria, and the development of unitary currents. Summation of unitary currents causes depolarization and activation of a dihydropyridine-resistant Ca2+ conductance that entrains pacemaker activity in a network of ICC, resulting in the active propagation of slow waves. Slow wave frequency is regulated by a variety of physiological agonists and conditions, and shifts in pacemaker dominance can occur in response to both neural and nonneural inputs. Loss of ICC in many human motility disorders suggests exciting new hypotheses for the etiology of these disorders.

Interstitial cells of cajal as pacemakers in the gastrointestinal tract.

We study the problem of controlling a general complex network toward an assigned synchronous evolution by means of a pinning control strategy We define the pinning controllability of the network in terms of the spectral properties of an extended network topology The roles of the control and coupling gains, as well as of the number of pinned nodes, are also discussed

/pdf/controllability-of-complex-networks-via-pinning-2tmspsmzw7.pdf

Controllability of complex networks via pinning.

Networks of interstitial cells of Cajal embedded in the musculature of the gastrointestinal tract are involved in the generation of electrical pacemaker activity for gastrointestinal motility1,2. This pacemaker activity manifests itself as rhythmic slow waves in membrane potential, and controls the frequency and propagation characteristics of gut contractile activity3–6. Mice that lack a functional Kit receptor fail to develop the network of interstitial cells of Cajal associated with Auerbach's plexus in the mouse small intestine7,8 and do not generate slow wave activity9,10. These cells could provide an essential component of slow wave activity (for example, a biochemical trigger that would be transferred to smooth muscle cells), or provide an actual pacemaker current that could initiate slow waves. Here we provide direct evidence that a single cell, identified as an interstitial cell of Cajal by light microscopy, electron microscopy and expression of Kit mRNA, generates spontaneous contractions and a rhythmic inward current that is insensitive to L-type calcium channel blockers. Identification of the pacemaker of gut motility will aid in the elucidation of the pathophysiology of intestinal motor disorders, and provide a target cell for pharmacological treatment.

Interstitial cells of Cajal generate a rhythmic pacemaker current

Proteins provide the structural framework of a cell and perform the enzymatic activities sustaining DNA replication and energy production. The hormones and growth factors that facilitate organ-to-organ communication are proteins as are the receptors and signaling intermediaries that integrate extracellular stimuli to intracellular action. As such, eukaryotic cells devote tremendous effort and energy to protein synthesis. The enzymes involved in protein synthesis have traditionally been described as cellular housekeepers. This was meant to imply that while they were necessary for cell viability, they were not thought to have a causal role in activating cell differentiation or neoplastic development the way that a transcription factor or hormone receptor might. However, two protein translation factors, protein initiation factor eIF4E and protein elongation factor eEF1A2, have been identified as important human oncogenes. This review summarizes recent work showing that protein initiation and elongation factors have important regulatory roles in cell growth, apoptosis, and tumorigenesis.

Not just for housekeeping: protein initiation and elongation factors in cell growth and tumorigenesis.

To reveal the unique intrinsic properties of interstitial cells of Cajal (ICC), morphological and electrophysiological characteristics of isolated ICC from the adult mouse small intestine were inve...

https://www.physiology.org/doi/pdf/10.1152/ajpgi.1999.277.2.G409

Generation of slow waves in membrane potential is an intrinsic property of interstitial cells of Cajal.

Since little is known about the role of P2Y receptors (purinoceptors) in duodenal mucosal bicarbonate secretion (DMBS), we sought to investigate the expression and function of these receptors in duodenal epithelium. Expression of P2Y2 receptors was detected by RT-PCR in mouse duodenal epithelium and SCBN cells, a duodenal epithelial cell line. UTP, a P2Y2-receptor agonist, but not ADP (10 μM), significantly induced murine duodenal short-circuit current and DMBS in vitro; these responses were abolished by suramin (300 μM), a P2Y-receptor antagonist, or 2-aminoethoxydiphenyl borate (2-APB; 100 μM), a store-operated channel blocker. Mucosal or serosal addition of UTP induced a comparable DMBS in wild-type mice, but markedly impaired response occurred in P2Y2 knockout mice. Acid-stimulated DMBS in vivo was significantly inhibited by suramin (1 mM) or PPADS (30 μM). Both ATP and UTP, but not ADP (1 μM), raised cytoplasmic-free Ca2+ concentrations ([Ca2+]cyt) with similar potencies in SCBN cells. ATP-induced [Ca2+]cyt was attenuated by U-73122 (10 μM), La3+ (30 μM), or 2-APB (10 μM), but was not significantly affected by nifedipine (10 μM). UTP (1 μM) induced a [Ca2+]cyt transient in Ca2+-free solutions, and restoration of external Ca2+ (2 mM) raised [Ca2+]cyt due to capacitative Ca2+ entry. La3+ (30 μM), SK&F96365 (30 μM), and 2-APB (10 μM) inhibited UTP-induced Ca2+ entry by 92, 87, and 94%, respectively. Taken together, our results imply that activation of P2Y2 receptors enhances DMBS via elevation of [Ca2+]cyt that likely results from an initial increase in intracellular Ca2+ release followed by extracellular Ca2+ entry via store-operated channel.

https://www.physiology.org/doi/pdf/10.1152/ajpgi.90314.2008

P2Y receptors mediate Ca2+ signaling in duodenocytes and contribute to duodenal mucosal bicarbonate secretion

The objective for this paper was to characterize the transient outward current (Ito) present in smooth muscle cells of the intestinal external muscularis. Two populations of cells were identified, one with a fast rate of Ito inactivation (τ 150 ms). The chord conductance for the fast Ito was smaller than the chord conductance of the slow Ito (0.5 ± 0.1 vs. 1.3 ± 0.1 nS pF−1, respectively). The inactivation was fitted by mono-exponentials to give a τ for the fast and slow Ito of 44 and 229 ms, respectively. Combined plots of voltage dependent activation and inactivation processes revealed voltage ranges where window currents were possible; a 20 mV range for the fast Ito from −56 to −36 mV and a 47 mV range for the slow Ito from −42 to +5 mV. The fast Ito recovered more quickly from inactivation than the slow Ito; τ(fast Ito) = 11 ± 4 ms compared to τ(slow Ito) = 42 ± 16 ms. The effect of different rates of depolarization on Ito activation was examined. The plots of peak currents evoked by different rates of depolarization were well fitted by inverse exponential functions. The fast Ito had a larger response to fast rates of depolarization by having a τ of 2 ± 1 mV ms−1 with maximal activation (95 % complete) at 5 mV ms−1. The slow Ito had a τ of 14 ± 9 mV ms−1 with maximal activation (95 % complete) at 42 mV ms−1. The properties of these currents suggest that the two transient outward currents may contribute differently to slow waves and action potentials generated by the smooth muscle cells.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2001.013557

Heterogeneous expression of transient outward currents in smooth muscle cells of the mouse small intestine

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