TY - JOUR. T1 - Dissociation of diabetes and obesity in mice lacking orphan nuclear receptor small heterodimer partner. AU - Park, Young Joo. AU - Kim, Seong Chul. AU - Kim, Jeehee. AU - Anakk, Sayeepriyadarshini. AU - Lee, Jae Man. AU - Tseng, Hsiu Ting. AU - Yechoor, Vijay. AU - Park, Junchol. AU - Choi, June Seek. AU - Jang, Hak Chul. AU - Lee, Ki Up. AU - Novak, Colleen M.. AU - Moore, David D.. AU - Lee, Yoon Kwang. PY - 2011/12. Y1 - 2011/12. N2 - Mixed background SHP -/- mice are resistant to diet-induced obesity due to increased energy expenditure caused by enhanced PGC-1α expression in brown adipocytes. However, congenic SHP -/- mice on the C57BL/6 background showed normal expression of PGC-1α and other genes involved in brown adipose tissue thermogenesis. Thus, we reinvestigated the impact of small heterodimer partner (SHP) deletion on diet-induced obesity and insulin resistance using congenic SHP -/- mice. Compared with their C57BL/6 wild-type counterparts, SHP -/- mice subjected to ...

TY - JOUR. T1 - The orphan nuclear receptor, liver receptor homolog-1, regulates cholesterol side-chain cleavage cytochrome P450 enzyme in human granulosa cells. AU - Kim, Joung W.. AU - Havelock, Jon C.. AU - Carr, Bruce R.. AU - Attia, George R.. PY - 2005/3/1. Y1 - 2005/3/1. N2 - After ovulation, there is a shift in ovarian steroidogenesis from an estrogen-producing ovarian follicle to a progesterone-producing corpus luteum. The first step in human ovarian steroidogenesis is catalyzed by cholesterol side-chain cleavage cytochrome P450 (CYP11A1) enzyme. Steroidogenic factor-1 is an orphan nuclear receptor that regulates several steroidogenic enzymes, including CYP11A1. Liver receptor homolog-1 (LRH-1) is another orphan nuclear receptor that is expressed in the human ovary. After ovulation there is a down-regulation in steroidogenic factor-1, which is associated with an up-regulation of LRH-1 expression. These changes coincide with increased level of CYP11A1 expression in human corpus luteum. ...

Inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (IP(7)), are water-soluble inositol phosphates that contain high energy diphosphate moieties on the inositol ring. Inositol hexakisphosphate kinase 1 (IP6K1) participates in inositol pyrophosphate synthesis, converting inositol hexakisphosphate (IP(6)) to IP(7). In the present study, we show that mouse embryonic fibroblasts (MEFs) lacking IP6K1 exhibit impaired DNA damage repair via homologous recombination (HR). IP6K1 knock-out MEFs show decreased viability and reduced recovery after induction of DNA damage by the replication stress inducer, hydroxyurea, or the radiomimetic antibiotic, neocarzinostatin. Cells lacking IP6K1 arrest after genotoxic stress, and markers associated with DNA repair are recruited to DNA damage sites, indicating that HR repair is initiated in these cells. However, repair does not proceed to completion because these markers persist as nuclear foci long after drug removal. A fraction of IP6K1-deficient MEFs

Voltage Dependent T Type Calcium Channel Subunit Alpha 1G (Voltage Gated Calcium Channel Subunit Alpha Cav3.1 or CACNA1G) - Drugs in Development, 2021 provides in depth analysis on Voltage Dependent T Type Calcium Channel Subunit Alpha 1G (Voltage Gated Calcium Channel Subunit Alpha Cav3.1 or CACNA1G) targeted pipeline therapeutics. The report provides comprehensive information complete with Analysis by Indications, Stage of Development, Mechanism of Action (MoA), Route of Administration (RoA) and Molecule Type. The report also covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases. Additionally, the report provides an overview of key players involved in Voltage Dependent T Type Calcium Channel Subunit Alpha 1G (Voltage Gated Calcium Channel Subunit Alpha Cav3.1 or CACNA1G) targeted therapeutics development and features dormant and discontinued projects. The report analyses the pipeline products across ...

Looking for online definition of neuronal dihydropyridine-sensitive calcium channel gamma subunit in the Medical Dictionary? neuronal dihydropyridine-sensitive calcium channel gamma subunit explanation free. What is neuronal dihydropyridine-sensitive calcium channel gamma subunit? Meaning of neuronal dihydropyridine-sensitive calcium channel gamma subunit medical term. What does neuronal dihydropyridine-sensitive calcium channel gamma subunit mean?

TY - JOUR. T1 - Inositol 1,4,5-trisphosphate receptor type 1 in granule cells, not in Purkinje cells, regulates the dendritic morphology of Purkinje cells through brain-derived neurotrophic factor production. AU - Hisatsune, Chihiro. AU - Kuroda, Yukiko. AU - Akagi, Takumi. AU - Torashima, Takashi. AU - Hirai, Hirokazu. AU - Hashikawa, Tsutomu. AU - Inoue, Takafumi. AU - Mikoshiba, Katsuhiko. PY - 2006/10/18. Y1 - 2006/10/18. N2 - Here, we show that cultured Purkinje cells from inositol 1,4,5-trisphosphate receptor type 1 knock-out (IP3R1KO) mice exhibited abnormal dendritic morphology. Interestingly, despite the huge amount of IP3R1 expression in Purkinje cells, IP3R1 in granule cells, not in the Purkinje cells, was responsible for the shape of Purkinje cell dendrites. We also found that BDNF application rescued the dendritic abnormality of IP3R1KO Purkinje cells, and that the increase in BDNF expression in response to activation of AMPA receptor (AMPAR) and metabotropic glutamate receptor ...

Inositol levels, maintained by the biosynthetic enzyme inositol-3-phosphate synthase (Ino1), are altered in a range of disorders, including bipolar disorder and Alzheimer's disease. To date, most inositol studies have focused on the molecular and cellular effects of inositol depletion without considering Ino1 levels. Here we employ a simple eukaryote, Dictyostelium discoideum, to demonstrate distinct effects of loss of Ino1 and inositol depletion. We show that loss of Ino1 results in an inositol auxotrophy that can be rescued only partially by exogenous inositol. Removal of inositol supplementation from the ino1(-) mutant resulted in a rapid 56% reduction in inositol levels, triggering the induction of autophagy, reduced cytokinesis, and substrate adhesion. Inositol depletion also caused a dramatic generalized decrease in phosphoinositide levels that was rescued by inositol supplementation. However, loss of Ino1 triggered broad metabolic changes consistent with the induction of a catabolic state that

Global Transient Receptor Potential Cation Channel Subfamily V Member 1 Market Report allows a reader to obtain an absolute evaluation of each influential factor involved in the Global Transient Receptor Potential Cation Channel Subfamily V Member 1 industry. The report primarily focuses to provide details of the market size which remains essential for every individual or company who has been performing in the market or interested for investment. The report includes a thorough evaluation of the historic and present status of the market and offers forecast estimations for market size, share, sales volume, and anticipations.. Request Global Transient Receptor Potential Cation Channel Subfamily V Member 1 Market Research Sample Report: https://www.marketresearchexplore.com/report/global-transient-receptor-potential-cation-channel-subfamily-v-member-1-market-analysis-2012-2017-and-forecast-2018-2023/87249#enquiry. In the report, the global Transient Receptor Potential Cation Channel Subfamily V ...

A complete separation of myo-inositol 1,4,5-[4,5-(32)P]trisphosphate prepared from human erythrocytes, and myo-[2-3H]inositol 1,3,4-trisphosphate prepared from carbachol-stimulated rat parotid glands [Irvine, Letcher, Lander & Downes (1984) Biochem. J. 223, 237-243], was achieved by anion-exchange high-performance liquid chromatography. This separation technique was then used to study the metabolism of these two isomers of inositol trisphosphate in carbachol-stimulated rat parotid glands. Fragments of glands were pre-labelled with myo-[2-3H]inositol, washed, and then stimulated with carbachol. At 5s after stimulation a clear increase in inositol 1,4,5-trisphosphate was detected, with no significant increase in inositol 1,3,4-trisphosphate. After this initial lag however, inositol 1,3,4-phosphate rose rapidly; by 15s it predominated over inositol 1,4,5-trisphosphate, and continued to rise so that after 15 min it was at 10-20 times the radiolabelling level of the 1,4,5-isomer. In contrast, after ...

Purpose : The peroxisome proliferator-activated receptor alpha agonist fenofibrate prevents progression of diabetic retinopathy, yet its mechanism of protective action is not known. Here, we tested the hypothesis that peroxisome proliferator-activated receptor alpha agonists promote retinal health in the setting of diabetes by inducing a unique transcriptional signature in the eye. Methods : First, we induced peroxisome proliferator-activated receptor alpha activity in the retina using systemically- or locally-introduced agonists and measured changes in canonical transcriptional targets. Second, we investigated retinal peroxisome proliferator-activated receptor responsiveness using a transgenic reporter system. Third, we performed a microarray analysis of transcript changes in whole retina after intravitreous delivery of several peroxisome proliferator-activated receptor alpha agonists and validated putative targets. Results : Canonical genes involved in lipid metabolism and beta-oxidation are ...

The effects of Li+ on carbachol-stimulated phosphoinositide metabolism were examined in rat cerebral-cortex slices labelled with myo-[2-3H]inositol. The muscarinic agonist carbachol evoked an enhanced steady-state accumulation of [3H]inositol monophosphate ([3H]InsP1), [3H]inositol bisphosphate ([3H]InsP2), [3H]inositol 1,3,4-trisphosphate ([3H]Ins(1,3,4)P3), [3H]inositol 1,4,5-trisphosphate ([3H]Ins(1,4,5)P3) and [3H]inositol tetrakisphosphate ([3H]InsP4). Li+ (5 mM), after a 10 min lag, severely attenuated carbachol-stimulated [3H]InsP4 accumulation while simultaneously potentiating accumulation of both [3H]InsP1 and [3H]InsP2 and, at least initially, of [3H]Ins(1,3,4)P3. These data are consistent with inhibition of inositol mono-, bis- and 1,3,4-tris-phosphate phosphatases to different degrees by Li+ in brain, but are not considered to be completely accounted for in this way. Potential direct and indirect mechanisms of the inhibitory action of Li+ on [3H]InsP4 accumulation are considered. The ...

TY - JOUR. T1 - Resistive training and chromium picolinate. T2 - Effects on inositols and liver and kidney functions in older adults. AU - Campbell, Wayne W.. AU - Joseph, Lyndon J.O.. AU - Ostlund, Richard E.. AU - Anderson, Richard A.. AU - Farrell, Peter A.. AU - Evans, William J.. PY - 2004/8. Y1 - 2004/8. N2 - This study assessed the effects of resistive training (RT) with or without chromium picolinate (Cr-pic) supplementation on the 24-h urinary excretions of myo-inositol, D-chiro-inositol, and pinitol, as well as clinical indices of kidney and liver functions. Thirty-two nondiabetic subjects, age 62 ± 4 y, performed RT twice weekly for 12 wk and consumed either 924 μg Cr/d as Cr-pic (n = 17) or a placebo (n = 15). Whole-body strength increased in all subjects by 20% and urinary chromium excretion increased 47-fold in the Cr-pic group. Urinary myo-inositol, D-chiro-inositol, and pinitol were not changed with RT or influenced by Cr-pic. Serum indices of kidney and liver functions were ...

Ca2+ release from the endoplasmic reticulum via inositol 1,4,5-triphosphate receptors (IP3Rs) regulate the growth and fate of human cardiac stem cells, but whether IP3Rs are operative in the derived myocyte progeny, and modulate Ca2+ homeostasis and electrical activity in this cell compartment is unknown. In this study, IP3R function was determined in left ventricular (LV) myocytes from normal human hearts declined for transplantation and integrated with assays in mouse cells. Transcripts for the three IP3R subtypes were identified in human LV myocytes by qRT-PCR and the expression of IP3R-2 was detected by Western blotting. In field-stimulated cells, IP3R activation via Gq-protein-coupled receptor agonists (endothelin-1, ATP) increased Ca2+ transient amplitude and contractility. Moreover, extra-systolic Ca2+ release and after-contractions were induced. These effects were prevented by IP3R blockade with xestopspongin-C. Similarly, myocytes obtained from mice infected in vivo with small hairpin ...

TY - JOUR. T1 - Correlation between inositol phospholipid hydrolysis and substance P receptors in rat CNS. AU - Mantyh, P. W.. AU - Pinnock, R. D.. AU - Downes, C. P.. AU - Goedert, M.. AU - Hunt, S. P.. PY - 1984/12/1. Y1 - 1984/12/1. N2 - The undecapeptide substance P is a neurotransmitter candidate in the mammalian central and peripheral nervous system1. Although the distribution of substance P-like immunoreactivity within the central nervous system (CNS) is well established2, the recent identification and autoradiographic localization of specific substance P-binding sites has revealed numerous areas of mismatch between peptide levels and numbers of such sites3-6. Previous studies have shown that substance P stimulates the hydrolysis of inositol phospholipids in peripheral tissues and in the hypothalamus7,8, probably through stimulation of a polyphosphoinositide-specific phospholipase C (refs 9-11). Inositol phospholipid hydrolysis has been implicated in the mobilization of cytosolic calcium ...

Stimulation of enzyme secretion in the pancreas on injection of a single dose of the cholinergic drug, pilocarpine, was associated with an increased incorporation of [2-3H]myoinositol into a lipid, which was previously characterized as phosphatidylinositol. Stimulation of enzyme secretion by hourly injection of the pancreozymin congener, caerulein, led to more increased phosphatidylinositol synthesis than with a single injection of pilocarpine. The amylase level of the pancreas remained at a low level as long as caerulein was injected, indicating continued stimulation of enzyme secretion even though increased phosphatidylinositol synthesis ceased after 6 h. Feeding gave the same stimulation of phosphatidylinositol synthesis as caerulein. The major synthesis of phosphatidylinositol in controls and the stimulation of phosphatidylinositol synthesis by pilocarpine was entirely confined to the microsome fraction throughout the experiments (up to 18 h). This shows that there is no flow of microsomal ...

TY - JOUR. T1 - Inositol pyrophosphates regulate endocytic trafficking. AU - Saiardi, Adolfo. AU - Sciambi, Catherine. AU - McCaffery, J. Michael. AU - Wendland, Beverly. AU - Snyder, Solomon H.. PY - 2002/10/29. Y1 - 2002/10/29. N2 - The high energy potential and rapid turnover of the recently discovered inositol pyrophosphates, such as diphosphoinositol-pentakisphosphate and bis-diphosphoinositol-tetrakisphosphate, suggest a dynamic cellular role, but no specific functions have yet been established. Using several yeast mutants with defects in inositol phosphate metabolism, we identify dramatic membrane defects selectively associated with deficient formation of inositol pyrophosphates. We show that this phenotype reflects specific abnormalities in endocytic pathways and not other components of membrane trafficking. Thus, inositol pyrophosphates are major regulators of endocytosis.. AB - The high energy potential and rapid turnover of the recently discovered inositol pyrophosphates, such as ...

The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARgamma); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARalpha, beta/delta, and gamma; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid ...

Here, we report the novel findings that in human adrenal glomerulosa cells both basal and stimulated rates of aldosterone production depend on voltage-gated calcium currents through T-type as well as L-type calcium channels. These findings are surprising because patch-clamp studies consistently report the basal membrane potential of ZG cells to be very hyperpolarized (around −80 mV), a potential at which high threshold L-type calcium channels are not expected to be active. In contrast, low threshold T-type calcium channels are activated at more hyperpolarized potentials and have a permissive window of steady-state activity at more hyperpolarized potentials (Perez-Reyes 2003). When stimulated by low physiological concentrations of Ang II or small increases in extracellular potassium, the membrane potential of ZG cells can rapidly reach the permissive voltage window for persistent T-type, but not L-type, calcium channel activity, that allows steady-state calcium influx (Rossier 2016). Therefore, ...

Cardiac myocytes express two types of voltage operated calcium currents, a high voltage activated (HVA) L-type, and a low voltage activated (LVA) T-type. Influx of calcium into the cell through the L-type channel is responsible for excitation-contraction coupling in the heart. The T-type calcium current has been associated with growth and differentiation in a number of different cell types. An atrial myocyte cell line (HL-1) that selectively expresses T-type calcium current was employed to show that inhibiting calcium influx through the T-type calcium channel inhibits cellular proliferation. Drug dosage studies demonstrate that the T-type calcium channel responsible for this effect is Cav 3.1. Furthermore, blocking the calcium influx through the T-type calcium channel arrests cells in the G2/M phase of the cell cycle. Interestingly, the proliferative effect of calcium influx through the T-type calcium channel appears to happen in the early G1 phase of the cell cycle ...

Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct-ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis

In the present study we have investigated the role of inositol 1,4,5-trisphosphate (IP3), functional IP3 receptors (IP3Rs) and the human homologue of the Drosophila transient receptor potential (Trp) channel, human Trp1 (hTrp1), in store-mediated Ca2+ entry (SMCE) in human platelets. Inhibition of IP3 recycling using Li+, or the inhibition of IP3Rs using xestospongin C, both resulted in the inhibition of SMCE activation following Ca2+ store depletion using thapsigargin. Co-immunoprecipitation experiments indicated that endogenously expressed hTrp1 couples with IP3R type II, but not types I or III, in platelets with depleted intracellular Ca2+ stores, but not in control, undepleted cells. These results provide strong evidence for the activation of SMCE by conformational coupling involving de novo association between IP3Rs and a plasma membrane channel in normal human cells.. ...

Metabolism of inositol 1,4,5-trisphosphate was investigated in permeabilized guinea-pig hepatocytes. The conversion of [3H]inositol 1,4,5-trisphosphate to a more polar 3H-labelled compound occurred rapidly and was detected as early as 5 s. This material co-eluted from h.p.l.c. with inositol 1,3,4,5 tetrakis[32P]phosphate and is presumably an inositol tetrakisphosphate. A significant increase in the 3H-labelled material co-eluting from h.p.l.c. with inositol 1,3,4-trisphosphate occurred only after a definite lag period. Incubation of permeabilized hepatocytes with inositol 1,3,4,5-tetrakis[32P]phosphate resulted in the formation of 32P-labelled material that co-eluted with inositol 1,3,4-trisphosphate; no inositol 1,4,5-tris[32P]phosphate was produced, suggesting the action of a 5-phosphomonoesterase. The half-time of hydrolysis of inositol 1,3,4,5-tetrakis[32P]phosphate of approx. 1 min was increased to 3 min by 2,3-bisphosphoglyceric acid. Similarly, the rate of production of material ...

Calcium signaling is essential for the differentiation of many cell types, including skeletal muscle cells, but its mechanisms remain elusive. Here we demonstrate a crucial role for nicotinic acid adenine dinucleotide phosphate (NAADP) signaling in skeletal muscle differentiation. Although the inositol trisphosphate pathway may have a partial role to play in this process, the ryanodine signaling cascade is not involved. In both skeletal muscle precursors and C2C12, cells interfering with NAADP signaling prevented differentiation, whereas promoting NAADP signaling potentiated differentiation. Moreover, siRNA knockdown of two-pore channels, the target of NAADP, attenuated differentiation. The data presented here strongly suggest that in myoblasts, NAADP acts at acidic organelles on the recently discovered two-pore channels to promote differentiation.

TY - JOUR. T1 - Inhibition of smooth muscle proliferation by urea-based alkanoic acids via peroxisome proliferator-activated receptor α-dependent repression of cyclin D1. AU - Ng, Valerie Y.. AU - Morisseau, Christophe. AU - Falck, John R.. AU - Hammock, Bruce D.. AU - Kroetz, Deanna L.. PY - 2006/11. Y1 - 2006/11. N2 - OBJECTIVE - Proliferation of smooth muscle cells is implicated in cardiovascular complications. Previously, a urea-based soluble epoxide hydrolase inhibitor was shown to attenuate smooth muscle cell proliferation. We examined the possibility that urea-based alkanoic acids activate the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and the role of PPARα in smooth muscle cell proliferation. METHODS AND RESULTS - Alkanoic acids transactivated PPARα, induced binding of PPARα to its response element, and significantly induced the expression of PPARα-responsive genes, showing their function as PPARα agonists. Furthermore, the alkanoic acids attenuated ...

By Jennifer Copley (Last Updated 30 March 2012). Some evidence suggests that inositol abnormalities may be a factor in autism. For example, Seelan et al. (2007) found altered myo-inositol levels in those with autistic spectrum disorders.. According to Levine et al. (1997): "Inositol is a precursor of the second messenger for some serotonin receptors, and has been reported effective in depression, panic disorder and obsessive-compulsive disorder. However a controlled double-blind crossover trial of inositol 200 mg/kg per day showed no benefit in 9 children with autism.". Overall, what little research has been conducted thus far suggests that inositol is probably not useful in treating most autistic symptoms, but may provide benefits when used to treat unpleasant conditions that often accompany autism, such as panic attacks, obsessive-compulsive disorder, and depression.. Other Autism Supplements. For more on the effectiveness of other supplements for treating autistic spectrum disorders, see the ...

Permeabilization of amoebae of Dictyostelium discoideum with saponin was found not to uncouple the chemotactic cell surface cyclic AMP receptors from inositol trisphosphate (IP3) formation, and stimulation of permeabilized amoebae with 50 nM-cyclic AMP produced peaks of IP3 at 5, 15 and 30 s in a manner comparable to that seen previously in non-permeabilized cells. The possible involvement of a GTP-binding protein (G-protein) in this IP3 signal transduction pathway was investigated by studying the effects on such permeabilized amoebae of added GTP and non-hydrolysable GTP analogues. While GDP produced only very minor effects, stimulation of the amoebae (in the absence of added cyclic AMP) with GTP or the non-hydrolysable GTP analogues GTP gamma S (guanosine 5′-O-(3-thio-triphosphate] and Gpp(NH)p (5′-guanylylimidodiphosphate) induced transient formation of IP3 in an oscillatory manner, with peaks similar in magnitude and timing to those elicited by cyclic AMP. A dose-response curve for GTP ...

The herbal remedy St. John's wort (SJW) is used in the treatment of mild depressive symptoms and is known for its drug-drug interaction potential when enhanced expression of CYP3A4 modifies clearance of concomitantly applied substrate drugs. Hyperforin is one constituent of SJW that alters CYP3A4 expression by activation of the nuclear receptor pregnane X receptor (PXR). However, little is known about the transmembrane transport of hyperforin. One membrane protein that modulates cellular entry of drugs is the organic anion-transporting polypeptide (OATP) 2B1. It was the aim of this study to test whether hyperforin interacts with this transport protein. Transport inhibition studies and competitive counterflow experiments suggested that hyperforin is a substrate of OATP2B1. This notion was validated by showing that the presence of OATP2B1 enhanced the hyperforin-induced PXR activation in cell-based luciferase assays. Moreover, in Caco-2 cells transcellular transport of the known OATP2B1 substrate ...

A number of clonal cell lines derived from a rat pituitary tumour, collectively termed GH cells, have retained a range of differentiated cell functions, including their ability to secrete the hormones prolactin and growth hormone in response to stimuli such as thyrotropin-releasing hormone (TRH). The mechanisms underlying this release process involve, at least in part, an increase in cytosolic free calcium levels, and the cells have proved useful as a model system in studies of receptor-controlled calcium mobilization. The initial response of the cells to the addition of TRH now appears to be the interaction of the occupied TRH receptor with a GTP-binding protein. A sophisticated signalling system is then activated which initially involves the phosphodiesteratic hydrolysis of phosphatidylinositol 4,5-bisphosphate to 1,2-diacylglycerol and inositol 1,4,5-trisphosphate. Both of these products are important intracellular messengers, and their formation leads to a plethora of biochemical and ...

COSTA, Flávia Martins et al. Proton magnetic resonance spectroscopy and perfusion magnetic resonance imaging in the evaluation of musculoskeletal tumors. Radiol Bras [online]. 2009, vol.42, n.4, pp.215-223. ISSN 1678-7099. https://doi.org/10.1590/S0100-39842009000400006.. OBJECTIVE: To assess the role of proton magnetic resonance spectroscopy and dynamic contrast-enhanced magnetic resonance imaging in the differentiation between malignant and benign musculoskeletal tumors. MATERIALS AND METHODS: Fifty-five patients with musculoskeletal tumors (27 malignant and 28 benign) were studied. The examinations were performed in a 1.5 T magnetic resonance scanner with standard protocol, and single voxel proton magnetic resonance spectroscopy with 135 msec echo time. The dynamic contrast study was performed using T1-weighted gradient-echo sequence after intravenous gadolinium injection. Timesignal intensity curves and slope values were calculated. The statistical analysis was performed with the Levene's ...

This clone is cross reactive with non-human primate neuroblastoma, including inositol triphosphate receptors I and III (< 0.01; < 0.001) (Physique 1Ai). IMR-32 neuroblastoma cells were more sensitive to CDDP, showing a significant decrease in cell viability after treatment with 10 M CDDP for 24 h (< 0.05); 1 and 10 M CDDP for 48 h (< 0.05 and < 0.001) and 72 h (< 0.001 and < 0.001) (Physique 1Bi). A third neuroblastoma cell line, NLF, was less sensitive to CDDP, i.e., exhibited a significant decrease in cell viability only after 48h treatment with 10 M CDDP (< 0.001; Supplementary Physique 1). Physique 1 Cell survival and apoptosis in neuroblastoma cells following CDDP or TOPO treatment TOPO (0.1 nM to 1 1 M) demonstrated a stronger cytotoxic effect compared to CDDP in all neuroblastoma cell lines tested and cell viability was significantly reduced in SH-SY5Y cell after 24 h, 48 h and 72 h of exposure (Determine 1Ai). The cytotoxic effects of TOPO were stronger in IMR-32 cells as compared with ...

Human peroxisome biogenesis disorders are lethal genetic diseases in which abnormal peroxisome assembly compromises overall peroxisome and cellular function. Peroxisomes are ubiquitous membrane-bound organelles involved in several important biochemical processes, notably lipid metabolism and the use of reactive oxygen species for detoxification. Using cultured cells, we systematically characterized the peroxisome assembly phenotypes associated with dsRNA-mediated knockdown of 14 predicted Drosophila homologs of PEX genes (encoding peroxins; required for peroxisome assembly and linked to peroxisome biogenesis disorders), and confirmed that at least 13 of them are required for normal peroxisome assembly. We also demonstrate the relevance of Drosophila as a genetic model for the early developmental defects associated with the human peroxisome biogenesis disorders. Mutation of the PEX1 gene is the most common cause of peroxisome biogenesis disorders and is one of the causes of the most severe form ...

Dantrolene and nimodipine dramatically reduce the number of activated microglia in the hippocampus and reduce the expression of various pro-inflammatory cytokines. It is not clear from our data whether the anti-inflammatory effects of dantrolene and nimodipine are due to direct action on the microglia themselves or an indirect effect via normalization of neuronal Ca+2 levels. Neurotoxicity of conditioned media from activated microglia is reduced when drugs blocking L-VDCCs or RyRs are applied to the microglia cultures [12-14]. However, the in vivo anti-inflammatory effects of these drugs are not so clear-cut. Following facial nerve transection, nimodipine treatment improves motor neuron survival without reducing microglia activation [53]. However, after ischemic-reperfusion injury, nimodipine does improve behavioral outcomes while concurrently reducing microglia activation [54]. Similarly, in vivo treatment with dantrolene is neuroprotective and improves behavioral outcomes in various in vivo ...

We have tested the periodate-oxidized ATP analogue 2′,3′-dialdehyde adenosine triphosphate (oATP) as a ligand for the skeletal muscle ryanodine receptor/Ca(2+)-release channel. Ca2+ efflux from passively loaded heavy sarcoplasmic reticulum vesicles of skeletal muscle is biphasic. oATP stimulates the initial phase of Ca2+ release in a concentration-dependent manner (EC50 160 microM), and the efflux proceeds with a half-time in the range 100-200 ms. This oATP-modulated initial rapid Ca2+ release was specifically inhibited by millimolar concentrations of Mg2+ and micromolar concentrations of Ruthenium Red, indicating that the effect of oATP was mediated via the ryanodine receptor. The purified Ca(2+)-release channel was incorporated into planar lipid bilayers, and single-channel recordings were carried out to verify a direct interaction of oATP with the ryanodine receptor. Addition of oATP to the cytoplasmic side activated the channel with an EC50 of 76 microM, which is roughly 30-fold higher ...

Abbreviations: CAPS, calcyphosine; CISK, cytokine-independent survival kinase; DAG, diacylglycerol; DCV, dense core vesicle; DGK, DAG kinase; EEA1, early endosomal antigen 1; ENTH, epsin N-terminal homology; ER, endoplasmic reticulum; IP3, myo-inositol 1,4,5-trisphosphate; LUV, large unilamellar vesicle; NSF, N-ethylmaleimide-sensitive factor; PH domain, pleckstrin homology domain; PI3K, phosphoinositide 3-kinase; PIP, phosphoinositide phosphate; PIP5K, PtdIns4P 5-kinase; PKC, protein kinase C; PLA, phospholipase A; PLC, phospholipase C; PLD, phospholipase D; PI-PLC, phosphoinositide-specific PLC; PtdOH, phosphatidic acid; PX domain, Phox homology domain; SARA, Smad anchor for receptor activation; SNAP, soluble NSF-attachment protein; SNARE, SNAP receptor; SCAMP2, secretory carrier membrane protein 2; VAMP, vesicle-associated membrane protein ...

Currents flowing through single dihydropyridine-sensitive Ca2+ channels were recorded from cell-attached patches on C2 myotubes. In the presence of dihydropyridine agonist to prolong the duration of single-channel openings, adding micromolar concentrations of lanthanum (La), cerium (Ce), neodymium (Nd), gadolinium (Gd), dysprosium (Dy), or ytterbium (Yb) to patch electrodes containing 110 mM BaCl2 caused the unitary Ba2+ currents to fluctuate between fully open and shut states. The kinetics of channel blockade followed the predictions of a simple open channel block model in which the fluctuations of the single-channel current arose from the entry and exit of blocking ions from the pore. Entry rates for all the lanthanides tested were relatively insensitive to membrane potential, however, exit rates depended strongly on membrane potential increasing approximately e-fold per 23 mV with hyperpolarization. Individual lanthanide ions differed in both the absolute rates of ion entry and exit: entry ...

TY - JOUR. T1 - Ligand for peroxisome proliferator-activated receptor γ (Troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. AU - Kubota, Tetsuya. AU - Koshizuka, Kozo. AU - Williamson, Elizabeth A.. AU - Asou, Hiroya. AU - Said, Jonathan W.. AU - Holden, Stuart. AU - Miyoshi, Isao. AU - Koeffler, H. Phillip. N1 - Copyright: Copyright 2007 Elsevier B.V., All rights reserved.. PY - 1998/8/1. Y1 - 1998/8/1. N2 - Troglitazone, a thiazolidinedione derivative, is a widely used antidiabetic drug that binds and activates peroxisome proliferator-activated receptor γ (PPARγ) and enhances insulin sensitivity. It induces differentiation of adipocytes, which highly express PPARγ. We report that human prostate cancer cells expressed PPARγ at prominent levels and normal prostate tissues had very low expression. Dose-response clonogenic assays of the PC-3 prostate cancer cell line with troglitazone showed an antiproliferative effect (ED50, 3 x 10-7 M) and ...

TY - JOUR. T1 - Proton magnetic resonance spectroscopy and intracranial tumours. T2 - Clinical perspectives. AU - Falini, Andrea. AU - Calabrese, Giovanna. AU - Origgi, Daniela. AU - Lipari, Susanna. AU - Triulzi, Fabio. AU - Losa, Marco. AU - Scotti, Giuseppe. PY - 1996. Y1 - 1996. N2 - Proton magnetic resonance spectroscopy ( 1H-MRS) was applied to characterize intracranial tumours of different hystological types. Seventy patients with intracranial neoplasms were studied before receiving surgery, radiotherapy or chemotherapy. All tumours were characterized by reduced or absent N-acetylaspartate and increased signal from choline-containing compounds. Distinctive patterns were observed only for primitive brain neo-plasms; high-grade gliomas were differentiated from low-grade ones by higher levels of choline-containing compounds. The metabolic aspects of metastatic lesions were similar to high-grade gliomas. These results, together with the limitations of 1H-MRS and future applications are ...

Calcium flux is required for the mammalian sperm acrosome reaction, an exocytotic event triggered by egg binding, which results in a dramatic rise in sperm intracellular calcium. Calcium-dependent membrane fusion results in the release of enzymes that facilitate sperm penetration through the zona pellucida during fertilization. We have characterized inositol 1,4,5-trisphosphate (IP3)-gated calcium channels and upstream components of the phosphoinositide signaling system in mammalian sperm. Peptide antibodies colocalized G alpha q/11 and the beta 1 isoform of phospholipase C (PLC beta 1) to the anterior acrosomal region of mouse sperm. Western blotting using a polyclonal antibody directed against purified brain IP3 receptor (IP3R) identified a specific 260 kD band in 1% Triton X-100 extracts of rat, hamster, mouse and dog sperm. In each species, IP3R immunostaining localized to the acrosome cap. Scatchard analysis of [3H]IP3 binding to rat sperm sonicates revealed a curvilinear plot with high ...

Chronic hypertension remains a major cause of global mortality and morbidity. It is a complex disease that is the clinical manifestation of multiple genetic, environmental, nutritional, hormonal, and aging-related disorders. Evidence supports a role for vascular aging in the development of hypertension involving an impairment in endothelial function together with an alteration in vascular smooth muscle cells (VSMCs) calcium homeostasis leading to increased myogenic tone. Changes in free intracellular calcium levels ([Ca] ) are mediated either by the influx of Ca from the extracellular space or release of Ca from intracellular stores, mainly the sarcoplasmic reticulum (SR). The influx of extracellular Ca occurs primarily through voltage-gated Ca channels (VGCCs), store-operated Ca channels (SOC), and Ca release-activated channels (CRAC), whereas SR-Ca release occurs through inositol trisphosphate receptor (IPR) and ryanodine receptors (RyRs). IPR-mediated SR-Ca release, in the form of Ca waves, ...

Inositol phosphate accumulation and adenylate cyclase activity were investigated in the cortex of young and aged ethanol-treated rats. Three months of ethanol treatment of young rats decreased maximal stimulation of inositol phosphate accumulation by carbachol by 26%, from 494 ± 76% of basal turnover in control animals to 396 ± 54% in ethanol-treated animals (mean ± SD). In aged rats ethanol-related changes were no longer observed but age-related changes were evident. EC50 was significantly higher than in young animals and maximal stimulation was significantly lower. Basal adenylate cyclase activity in cortical membranes of all groups of animals was not different. Forskolin-stimulated adenylate cyclase activity was not affected by ethanol treatment, but was higher in aged animals. The activity of forskolin-stimulated adenylate cyclase in the presence of carbachol was higher in both young and aged ethanol-treated animals, when compared to young controls. These results suggest that both ethanol ...

TY - JOUR. T1 - Nitric oxide-dependent activation of CaMKII increases diastolic sarcoplasmic reticulum calcium release in cardiac myocytes in response to adrenergic stimulation. AU - Curran, Jerry. AU - Tang, Lifei. AU - Roof, Steve R.. AU - Velmurugan, Sathya. AU - Millard, Ashley. AU - Shonts, Stephen. AU - Wang, Honglan. AU - Santiago, Demetrio. AU - Ahmad, Usama. AU - Perryman, Matthew. AU - Bers, Donald M. AU - Mohler, Peter J.. AU - Ziolo, Mark T.. AU - Shannon, Thomas R.. PY - 2014/2/3. Y1 - 2014/2/3. N2 - Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca2+ leak) through ryanodine receptors. Beta-adrenergic (β-AR) tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII) and the subsequent phosphorylation of the ryanodine receptor. When b-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent ...

TY - JOUR. T1 - Canonical transient receptor potential 3 channels activate NF-κB to mediate allergic airway disease via PKC-α/IκB-α and calcineurin/IκB-β pathways. AU - Song, Tengyao. AU - Zheng, Yun Min. AU - Vincent, Peter A.. AU - Cai, Dongsheng. AU - Rosenberg, Paul. AU - Wang, Yong Xiao. PY - 2016/1/1. Y1 - 2016/1/1. N2 - The purpose of this study was to determine the role of canonical transient receptor potential 3 (TRPC3) channel in allergen-induced airway disease (AIAD) and its underlying signaling mechanisms. The procedures included (1) intravenous injection of lentiviral TRPC3 channel or nonsilencing short hairpin ribonucleic acid (shRNA) to make the channel knockdown (KD) or control mice, (2) allergen sensitization/challenge to induce AIAD, (3) patch-clamp recording and Ca2+ imaging to examine the channel activity, and (4) gene manipulations and other methods to determine the underlying signaling mechanisms. The findings are that (1) intravenous or intranasal delivery of TRPC3 ...

Cyclic nucleotide-gated (CNG)1 ion channels are key players in visual and olfactory signal transduction pathways (reviewed in Lancet, 1986; Yau and Baylor, 1989; Zufall et al., 1994). Although they are only weakly voltage dependent, CNG channels have regions of sequence similarity with voltage-gated channels (Jan and Jan, 1990). One region of high conservation between CNG channels and voltage-gated channels is the P region, thought to line a portion of the ion-conducting pore. Shaker K+ channels that have had portions of their P region replaced with the corresponding region from CNG channels take on many of the permeation properties of CNG channels (Heginbotham et al., 1992). These chimeric channels become permeable to Na+ as well as to K+ and become blocked by the divalent cations Mg2+ and Ca2+. Like voltage-gated channels, CNG channels are thought to possess multi-ion pores (Furman and Tanaka, 1990; Sesti et al., 1995). The external divalent cation binding site is thought to involve the E363 ...

TY - JOUR. T1 - Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction. AU - Abe, T.. AU - Sugihara, H.. AU - Nawa, H.. AU - Shigemoto, R.. AU - Mizuno, N.. AU - Nakanishi, S.. N1 - Copyright: Copyright 2004 Elsevier B.V., All rights reserved.. PY - 1992. Y1 - 1992. N2 - A cDNA clone for a new metabotropic glutamate receptor, mGluR5, was isolated through polymerase chain reaction-mediated DNA amplification by using primer sequences conserved among the metabotropic glutamate receptor (mGluR) family and by the subsequent screening of a rat brain cDNA library. The cloned receptor consists of 1171 amino acid residues and exhibits a structural architecture common to the mGluR family, possessing a large extracellular domain preceding the seven putative membrane-spanning segments. mGluR5 shows the highest sequence similarity to mGluR1 among the mGluR members and is coupled to the stimulation of phosphatidylinositol ...

TY - JOUR. T1 - An RNA-interacting protein, SYNCRIP (heterogeneous nuclear ribonuclear protein Q1/NSAP1) is a component of mRNA granule transported with inositol 1,4,5-trisphosphate receptor type 1 mRNA in neuronal dendrites. AU - Bannai, Hiroko. AU - Fukatsu, Kazumi. AU - Mizutani, Akihiro. AU - Natsume, Tohru. AU - Iemura, Shuin Ichiro. AU - Ikegami, Tohru. AU - Inoue, Takafumi. AU - Mikoshiba, Katsuhiko. PY - 2004/12/17. Y1 - 2004/12/17. N2 - mRNA transport and local translation in the neuronal dendrite is implicated in the induction of synaptic plasticity. Recently, we cloned an RNA-interacting protein, SYNCRIP (heterogeneous nuclear ribonuclear protein Q1/NSAP1), that is suggested to be important for the stabilization of mRNA. We report here that SYNCRIP is a component of mRNA granules in rat hippocampal neurons. SYNCRIP was mainly found at cell bodies, but punctate expression patterns in the proximal dendrite were also seen. Time-lapse analysis in living neurons revealed that the granules ...

TY - JOUR. T1 - Luteinizing hormone stimulates the formation of inositol trisphosphate and cyclic AMP in rat granulosa cells. Evidence for phospholipase C generated second messengers in the action of luteinizing hormone. AU - Davis, J. S.. AU - Weakland, L. L.. AU - West, L. A.. AU - Farese, R. V.. PY - 1986/1/1. Y1 - 1986/1/1. N2 - The following studies were conducted to determine whether luteinizing hormone (LH), a hormone which increases cellular levels of cyclic AMP, also provokes increases in 'second messengers' derived from inositol lipid metabolism (i.e. inositol phosphates and diacylglycerol). Rat granulosa cells isolated from mature Graafian follicles were prelabelled for 3 h with myo-[2-3H]inositol. LH provoked rapid (5 min) and sustained (up to 60 min) increases in the levels of inositol mono-, bis-, and trisphosphates (IP, IP2 and IP3, respectively). Time course studies revealed that IP3 was formed more rapidly than IP2 and IP following LH treatment. The response to LH was ...

In sea urchin eggs, Ca2+ mobilization by nicotinic acid adenine dinucleotide phosphate (NAADP) potently self-inactivates but paradoxically induces long-term Ca2+ oscillations. We investigated whether NAADP-induced Ca2+ oscillations arise from the recruitment of other Ca2+ release pathways. NAADP, inositol trisphosphate (IP3) and cyclic ADP-ribose (cADPR) all mobilized Ca2+ from internal stores but only NAADP consistently induced Ca2+ oscillations. NAADP-induced Ca2+ oscillations were partially inhibited by heparin or 8-amino-cADPR alone, but eliminated by the presence of both, indicating a requirement for both IP3- and cADPR-dependent Ca2+ release. Thapsigargin completely blocked IP3 and cADPR responses as well as NAADP-induced Ca2+ oscillations, but only reduced the NAADP-mediated Ca2+ transient. Following NAADP-mediated release from this Ca2+ pool, the amount of Ca2+ in the Ca2+-induced Ca2+ release stores was increased. These results support a mechanism in which Ca2+ oscillations are initiated by Ca2

DDT1 MF-2 cells, which are derived from hamster vas deferens smooth muscle, contain alpha 1-adrenergic receptors (54,800 +/- 2700 sites per cell) that are coupled to stimulation of inositol phospholipid metabolism. Incubation of these cells with tumor-promoting phorbol esters, which stimulate calcium- and phospholipid-dependent protein kinase, leads to a marked attenuation of the ability of alpha 1-receptor agonists such as norepinephrine to stimulate the turnover of inositol phospholipids. This turnover was measured by determining the 32P content of phosphatidylinositol and phosphatidic acid after prelabeling of the cellular ATP pool with 32Pi. These phorbol ester-treated cells also displayed a decrease in binding affinity of cellular alpha 1 receptors for agonists with no change in antagonist affinity. By using affinity chromatography on the affinity resin Affi-Gel-A55414, the alpha 1 receptors were purified approximately equal to 300-fold from control and phorbol ester-treated 32Pi-prelabeled ...

We have, in the accompanying work, demonstrated the coexistence of M2 and M3 muscarinic receptors in the circular smooth muscle of canine colon. In the present study, the effects of muscarinic receptor stimulation on phosphoinositide turnover and adenylate cyclase activity were examined. In myo-[3H]inositol-labeled circular smooth muscle strips, carbachol caused a concentration-dependent (EC50 = 5 microM) increase in [3H]inositol phosphate production. The more M3 receptor-selective muscarinic antagonist pirenzepine (KB = 53 nM) was approximately 60 times more potent than the more M2-selective agent AF-DX 116 (KB = 3 microM) in blocking carbachol-elicited accumulation of [3H]inositol phosphates. The carbachol-stimulated increase in [3H]inositol phosphate accumulation was not affected by pretreatment of the tissue with pertussis toxin (200 ng/ml, 3 hr). Within the first minute, carbachol (100 microM) caused a rapid and transient increase of [3H]inositol 1,4,5-trisphosphate production that ...

Nicotinic acid adenine dinucleotide phosphate (NAADP) has recently been shown to act as a second messenger controlling intracellular Ca responses in mammalian cells. Many questions remain regarding this signaling pathway, including the role of the ryanodine receptor (RyR) in NAADP-induced Ca transients. Furthermore, the exact metabolic pathway responsible for the synthesis of NAADP in vivo has not been determined. Here, we demonstrate that the NAADP mediated Ca release system is present in human myometrial cells. We also demonstrate that human myometrial cells use the NAADP second messenger system to generate intracellular Ca transients in response to histamine. It has been proposed in the past that the NAADP system in mammalian cells is dependent on the presence of functional RyRs. Here, we observed that the histamine-induced Ca transients are dependent on both the NAADP and inositol 1,4,5-trisphosphate signaling pathways but are independent of RyRs. The enzyme CD38 has been shown to catalyze ...