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PubMed2006

Stored Ca2+ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: An initiation mechanism for capacitive Ca2+ entry.

Stromal interaction molecule 1 (STIM1) has recently been identified as a key player in store-operated Ca2+ entry. Endoplasmic reticulum (ER) luminal Ca2+ depletion results in STIM1 redistribution from ER membrane homogeneity to distinctly localized aggregates near the plasma membrane; these changes precede and are linked to cytoplasmic Ca2+ influx via Ca2+ release-activated channels (CRACs). The molecular mechanisms initiating ER STIM1 redistribution and plasma membrane CRAC activity are not well understood. We recombinantly expressed the Ca2+-sensing region of STIM1 consisting of the EF-hand together with the sterile alpha-motif (SAM) domain (EF-SAM) to investigate its Ca2+-related conformational and biochemical features. We demonstrate that Ca2+-loaded EF-SAM (holo) contains high alpha-helicity, whereas EF-SAM in the absence of Ca2+ (apo) is much less compact. Accordingly, the melting temperature (Tm) of the holoform is approximately 25 degrees C higher than apoform; heat and urea-derived thermodynamic parameters indicate a Ca2+-induced stabilization of 3.2 kcal mol(-1). We show that holoEF-SAM exists as a monomer, whereas apoEF-SAM readily forms a dimer and/or oligomer, and that oligomer to monomer transitions and vice versa are at least in part mediated by changes in surface hydrophobicity. Additionally, we find that the Ca2+ binding affinity of EF-SAM is relatively low with an apparent dissociation constant (Kd) of approximately 0.2-0.6 mM and a binding stoichiometry of 1. Our results suggest that EF-SAM actively participates in and is the likely the molecular trigger initiating STIM1 punctae formation via large conformational changes. The low Ca2+ affinity of EF-SAM is reconciled with the confirmed role of STIM1 as an ER Ca2+ sensor.

Calcium↗
PubMed2006

S-adenosylmethionine (SAM)-accumulating sake yeast suppresses acute alcohol-induced liver injury in mice.

The suppressive effects on acute alcoholic liver injury of S-adenosylmethionine (SAM) and the sake yeast, Saccharomyces cerevisiae Kyokai No. 9, have been shown previously. To enhance the suppression of acute alcoholic liver injury by sake yeast, we prepared SAM-accumulating sake yeast (SAM yeast). Male C57BL/6 mice that had been fed on a diet containing 0.25% SAM yeast or sake yeast for two weeks received three doses of ethanol (5 g/kg BW). In the mice fed on the SAM yeast, the ethanol-induced increases in both triglyceride (TG) and alanine aminotransferase (ALT) were significantly repressed. In addition, the SAM yeast-fed mice did not show an ethanol-induced decrease in hepatic SAM level, suggesting that a disorder of methionine metabolism in the liver caused by ethanol was relieved by the SAM yeast. These results suggest that the SAM yeast had a stronger effect suppressing acute alcoholic liver injury in mice than the sake yeast.

Alanine Transaminase↗
PubMed2004

Localization of interictal spikes using SAM(g2) and dipole fit.

SAM(g2) is an automated analysis that transforms the MEG data into a functional image of spike-like activity, giving the source waveforms for those locations. Since the source waveforms estimated by SAM have higher signal-to-noise ratio (SNR) than does the raw MEG data, it is possible to automatically mark the location and timing of each spike for comparisons with dipole fit procedures. Both SAM(g2) and equivalent current dipole (ECD) fits were used to analyze MEG interictal spike recordings in 10 patients with cortical dysplasias and medial temporal lobe epilepsy. The ECD fit locations obtained by manual spike classification and latency marking were compared with those found by automated SAM(g2) procedures. When the SNR of interictal activity was high (compared to the background) with a clear single focus, there was excellent agreement between the ECD cluster location and the SAM(g2) maximum. However, when the SNR of spikes was low, manual single ECD location scatter was larger than SAM(g2) reconstructions. When multiple independent interictal spike loci were present, there was some disagreement between SAM(g2) and ECD scatter in the cases of low SNR spikes. When SAM(g2) indicated multiple coupled spike loci, the residual variance for the dipole fit was high and its scatter unacceptably large--even for multiple dipole models. This study demonstrates that SAM(g2) is equivalent to ECD fit for localizing interictal spikes when there is a single locus and good SNR. Further studies are required to validate cases in which there are multiple spike loci or poor SNR.

Action Potentials↗
PubMed1998

Methamphetamine treatment affects blood and liver S-adenosylmethionine (SAM) in mice. Correlation with dopamine depletion in the striatum.

Methamphetamine (METH) is a major drug of abuse which causes neurotoxicity by depleting dopamine, its metabolites, high-affinity dopamine uptake sites and tyrosine hydroxylase activity in the striatum. Dopamine depletion and reduced dopamine transit are associated with depression. S-Adenosylmethionine (SAM) is the chief methyl donor used in dopamine and other neurotransmitter metabolism in mammals. Low SAM is associated with depression and other psychological and neurological disorders in humans. SAM is used to treat depression and some other neurological and psychiatric disorders. The present study was designed to determine if single or multiple doses of METH induce alterations in blood or liver SAM in mice and if these correlate with dopamine levels in the striatum. Adult male C57 mice were injected intraperitoneally with either single (1 x 40 mg/kg) or multiple (4 x 10 mg/kg) doses of METH. Animals were sacrificed at various intervals. A single injection of METH resulted in slightly higher blood SAM levels at 4 hr. Multiple doses of METH resulted in decreased hepatic and blood SAM levels at 72 hr. Blood SAM returned to control levels by 1 wk. Published work shows that dopamine levels increase hours after a single injection of METH, whereas dopamine decreases days after multiple injections of METH. These present data clearly demonstrate that METH dosing leads to significant alterations in liver and blood SAM and that these changes in SAM levels correlate with changes in striatal dopamine levels.

Animals↗
PubMed1988

Age-related deterioration of ability of acquisition in memory and learning in senescence accelerated mouse: SAM-P/8 as an animal model of disturbances in recent memory.

Memory, learning and behavior of senescence accelerated mouse (SAM-P/8) were investigated by using passive avoidance response, T-maze and open field and the findings were compared with those from senescence resistant mouse (SAM-R/1 control). SAM-P/8 mice showed a remarkable age-related deterioration in ability of memory and learning in passive avoidance response. This age-related memory and learning deficit was linked to a deterioration in the ability of acquisition and was not due to impairment in the ability of retention and hyperactivity, as observed in the open field. In the alternation T-maze tests, SAM-P/8 showed as high a rate of alternations as did the SAM-R/1 and in the T-maze avoidance tests, SAM-P/8 also showed as intact a memory ability as seen in the SAM-R/1, despite a memory deficit in the passive avoidance response. Thus, SAM-P/8 may prove to be a pertinent model for researching mechanisms related to the memory deficit seen in senile humans.

Aging↗
PubMed1991

Elevated concentrations of beta-nerve growth factor in selected tissues from senescence-accelerated mice (SAM-P/8).

Levels of the beta-subunit of nerve growth factor (beta-NGF) were determined in various tissues from senescence-accelerated mice (SAM-P/8) and compared with those from senescence-resistant control mice (SAM-R/1) at 4 months of age. (1) In SAM-P/8, the testis was 30% larger in terms of wet weight than that from SAM-R/1, whereas the adrenal glands from males and females were smaller than those from the respective controls by 45% and 20%, respectively. (2) About 70% of SAM-P/8 individuals had high concentrations of testosterone in serum (greater than 5ng/ml). (3) In SAM-P/8, endogenous levels of beta-NGF were significantly higher in the adrenal gland (20 and 7 times higher on average in males and females, respectively), in the thymus (100 and 5 times higher in males and females, respectively) and in the testis (500 times higher) than those in the control tissues. In other tissues there were little or no differences in terms of levels of beta-NGF. (4) Morphological changes in the adrenal gland, thymus and testis of SAM-P/8 mice were not as marked as expected from the elevated levels of beta-NGF in these tissues. (5) These results show that, in SAM-P/8 mice at 4 months of age, an elevation in the endogenous level of beta-NGF has already occurred in some peripheral tissues before senescence becomes accelerated.

Adrenal Glands↗
PubMed1993

Age changes in visceral content of glutathione in the senescence accelerated mouse (SAM).

Free radical formation is known to play a role in the aging processes. However, it is still disputable whether the scavengers of free radicals including glutathione (GSH) decrease during aging. The senescence accelerated mice (SAM) are known to show age-related disorders. Some of these syndromes were thought to be closely associated with oxidative damages. Using the two strains of SAM, SAM-R/1 and SAM-P/2, we examined age-related changes in GSH content in the tissues and its oxidation. In the eye, GSH levels were significantly decreased at the age of 16 months in SAM-P/2 and female SAM-R/1. The ratio of oxidized glutathione to total GSH increased, indicating GSH may play an important role in the eyes. But there were no remarkable age-related changes in GSH contents of other tissues such as liver, kidney and lung in both SAM-R/1 and SAM-P/2. These data suggest that the GSH level of the tissues in general can not be a proper indicator for senescence.

Aging↗
PubMedDate not supplied

Age-related changes in barrier function in mouse brain I. Accelerated age-related increase of brain transfer of serum albumin in accelerated senescence prone SAM-P/8 mice with deficits in learning and memory.

The time course of brain accumulation of radiolabelled human serum albumin ((125)I-HSA) injected intravenously and the transfer of (125)I-HSA from blood to brain were evaluated in DDD mice using a double isotope technique. The brain accumulation of (125)I-HSA at 3 and 9 h but not at 24 h postinjection and the brain transfer rates were significantly higher in 22-month-old DDD mice than in 4-month-old ones. The brain transfer rates of (125)I-HSA were measured also in senescence accelerated prone mice (SAM-P/8) with age-related deficits in learning and memory, and in senescence accelerated resistant mice (SAM-R/I) without these deficits. The brain transfer rates were significantly higher in 13-month-old SAM-P/8 and 22-month-old SAM-R/1 than in 3-month-old mice of the same strains, respectively. The mean brain transfer rates in five regions observed in 22-month-old DDD mice, 22-month-old SAM-R/1 and 13-month-old SAM-P/8 increased by 31%, 41% and 51% compared with corresponding values in 3- or 4-month-old mice of the same strains. DDD mice and SAM-R/1 mice with normal characteristics of aging showed similar age-related significant changes in brain transfer rates. Age-related increase in the brain transfer rate was manifested at the youngest age in SAM-P/8 among the three strains examined. These findings show that the transfer of human serum albumin into the mouse brain increases with aging and suggest that the barrier function in the mouse brain against macromolecules changes with aging.

Journal Article↗
PubMed2006

Responses of inferior colliculus neurons to SAM tones located in inhibitory response areas.

In order to examine the effect of inhibition on processing auditory temporal information, responses of single neurons in the inferior colliculus of the chinchilla to sinusoidally amplitude-modulated (SAM) tones alone and the presence of a steady-state tone were obtained. The carrier frequency of the SAM tone was either the characteristic frequency (CF) or a frequency in the inhibitory response area of a studied neuron. When the carrier frequency was set to the neuron's CF, neurons responded in synchrony to the SAM-tone envelope, as expected. When the carrier frequency was set to a frequency at which pure tones produced inhibition, SAM tones elicited little or no response, also as expected. However, when the same SAM tone was paired with a pure tone whose frequency was set to the neuron's CF, responses synchronized to the SAM tone envelope were obtained. These modulated responses were typically one-half cycle out-of-phase with the response to the SAM tone at CF, suggesting that they arose from cyclic inhibition and release from inhibition by the SAM tone. The results demonstrate that the representation of temporal information by inferior colliculus neurons is influenced by temporally-patterned inhibition arising from locations remote from CF.

Acoustic Stimulation↗
PubMed2004

Fishing of beta-amylase with a SAM of alpha-cyclodextrin-poly- (ethylene glycol) conjugate.

Alpha-cyclodextrin (alpha-CD) with an amino group was conjugated to an alpha, omega-dicarboxylated poly(ethylene glycol) (PEG). The inhibition constant (Ki) of the alpha-CD-PEG conjugate for the catalysis by beta-amylase was larger than that of alpha-CD, due to a steric obstruction of the PEG moiety to the binding of alpha-CD moiety to beta-amylase. alpha-CD-PEG was further modified with cystamine (CD-PEG-Cys) or cysteamine methyl disulfide (CD-PEG-MDS), and the disulfide-carrying alpha-CD-PEG was accumulated on a gold surface as a self-assembled monolayer (SAM). The binding of beta-amylase to the alpha-CD-PEG SAM was followed by a decrease in cathodic peak current in the voltammogram of hydroquinone as a probe using a cyclic voltammetry (CV). The beta-amylase bound to the alpha-CD-PEG SAM was desorbed by the addition of free alpha-CD, and the ratio of desorbed beta-amylase from the SAM of alpha-CD-PEG-Cys to the total amount of the enzyme bound to the SAM was 40% whereas that from the alpha-CD-PEG-MDS SAM was 83-85%. The percentage of desorption was increased to 100% by the treatment of the alpha-CD-PEG-MDS SAM-carrying electrode with 2-hydroxyethyldisulfide prior to the immersion in the enzyme solution. Adsorption and desorption processes of beta-amylase to the surface of alpha-CD-PEG-MDS SAM were clearly observed using localized surface plasmon resonance absorption spectroscopy. The binding constant of the enzyme to the surface-confined alpha-CD-PEG was much larger than that to free alpha-CD, probably due to a large local concentration of the alpha-CD moiety on the gold surface.

Catalysis↗
PubMed2005

Saccharomyces cerevisiae Ste50 binds the MAPKKK Ste11 through a head-to-tail SAM domain interaction.

In Saccharomyces cerevisiae, signal transduction through pathways governing mating, osmoregulation, and nitrogen starvation depends upon a direct interaction between the sterile alpha motif (SAM) domains of the Ste11 mitogen-activated protein kinase kinase kinase (MAPKKK) and its regulator Ste50. Previously, we solved the NMR structure of the SAM domain from Ste11 and identified two mutants that diminished binding to the Ste50 SAM domain. Building upon the Ste11 study, we present the NMR structure of the monomeric Ste50 SAM domain and a series of mutants bearing substitutions at surface-exposed hydrophobic amino acid residues. The mid-loop (ML) region of Ste11-SAM, defined by helices H3 and H4 and the end-helix (EH) region of Ste50-SAM, defined by helix H5, were sensitive to substitution, indicating that these two surfaces contribute to the high-affinity interaction. The combination of two mutants, Ste11-SAM-L72R and Ste50-SAM-L69R, formed a high-affinity heterodimer unencumbered by competing homotypic interactions that had prevented earlier NMR studies of the wild-type complex. Yeast bearing mutations that prevented the heterotypic Ste11-Ste50 association in vitro presented signaling defects in the mating and high-osmolarity growth pathways.

Amino Acid Sequence↗
PubMed2003

CUC1 gene activates the expression of SAM-related genes to induce adventitious shoot formation.

CUP-SHAPED COTYLEDON (CUC)1 encodes members of the NAC family. These are functionally redundant genes that are involved in shoot apical meristem (SAM) formation and cotyledon separation during embryogenesis in Arabidopsis. We analyzed transgenic plants overexpressing CUC1 (35S::CUC1). The cotyledons of these transgenic seedlings regularly had two basal lobes, small and round epidermal cells between the sinuses, and adventitious SAMs on the adaxial surface of this region. This suggests that CUC1 promotes adventitious SAM formation by maintaining epidermal cells in an undifferentiated state. In 35S::CUC1 cotyledons, the class I knotted-like homeobox (KNOX) genes, including SHOOT MERISTEMLESS (STM) and BREVIPEDICELLUS (BP), which are involved in SAM formation and/or maintenance, were ectopically expressed before adventitious SAM formation. In stm mutants, ectopic expression of CUC1 could not induce adventitious SAMs, whereas they continued to be observed in bp mutants. These results suggest that STM, but not BP, is necessary for the formation of adventitious SAMs in 35S::CUC1 cotyledons. Furthermore, we examined the relationship between CUC1 and ASYMMETRIC LEAVES (AS)1 and AS2. The as1 and as2 mutations genetically enhance 35S::CUC1 phenotypes even in the absence of STM function. Interestingly, the as1 mutation can partially rescue the mutant vegetative development phenotypes in the cuc1 cuc2 double mutant. Our results suggest that CUC1 positively regulates SAM formation not only through STM but also through an STM-independent pathway that is negatively regulated by AS1 and AS2.

Arabidopsis↗
PubMed1992

K-sam gene encodes secreted as well as transmembrane receptor tyrosine kinase.

K-sam was first identified as a gene amplified in the stomach cancer cell line KATO-III. The size of the major transcript of the K-sam gene was 3.5 kilobases in KATO-III cells, and we have previously shown that K-sam encodes a receptor tyrosine kinase that belongs to the heparin-binding growth factor receptor, or fibroblast growth factor receptor, gene family. The K-sam gene expresses multiple sizes of mRNAs in brain tissue, the immature teratoma cell line NCC-IT, and KATO-III. RNA blot analyses with a variety of K-sam probes indicate that there are at least four classes of K-sam mRNAs. Three types of K-sam cDNAs in addition to the previously reported type of K-sam cDNA were isolated, and their nucleotide sequences encode a full-length transmembrane receptor, a secreted receptor with a tyrosine kinase domain, and a secreted receptor without a tyrosine kinase domain.

Base Sequence↗
PubMed1985

Chronic food restriction modulates the advance of senescence in the senescence accelerated mouse (SAM).

The effects of chronic food restriction on grading scores of senescence, deposition of senile amyloid (ASSAM), mean life span and 10th decile were investigated by using animal models for accelerated senescence (SAM-P/1) and for normal aging (SAM-R/1). The experimental groups consisted of control (ad libitum fed), 80% (fed 80% of control intake), and 60% (fed 60% of control intake) groups. The grading score of SAM-P/1 mice was significantly improved in the 60% group, but not in the 80% group, compared to the control group. The grading score of SAM-R/1 mice, however, was significantly less than that in the control group in both the 60 and 80% groups. In SAM-P/1 mice liver, skin and testis, the severity of senile amyloid deposition was significantly less with 40% food restriction (60% group) than in the control group. A restriction of 20% (80% group) had no influence on amyloid deposition. A definite tendency to prolong mean life span (24.3%) and 10th decile (65.9%, mean life span of the last 10th of survivors of a group) was observed in the 60% group of SAM-P/1 mice, but the changes were not statistically significant. In the 80% group of SAM-P/1 mice and also in either restriction group of SAM-R/1 mice, however, such a tendency was not evident. These results indicate that 40% food restriction modulates the advance of senescence in these mice.

Aging↗
PubMed1989

Spontaneous spongy degeneration of the brain stem in SAM-P/8 mice, a newly developed memory-deficient strain.

A spontaneous spongy degeneration of the brain stem and spinal cord was discovered in a murine model of accelerated senescence (SAM), cared for under both conventional (SAM-P/8) and specific pathogen-free (SAM-P/8/Ta) conditions. SAM-P/8 and SAM-P/8/Ta showed no clinical neurological abnormalities, yet there was a deterioration in learning and memory abilities. Light microscopic examination revealed a spongy degeneration in the brain stem and spinal cord, in the reticular formation, and proliferation of hypertrophic astrocytes in the spongy area. The spongiform degeneration progressed with advancing age from four to eight months, after which the entire brain was involved. Astrocytosis increased with advancing degeneration. Ultrastructurally, mild dendritic swelling occurred at one month of age. At two months of age, moderate postsynaptic swelling and a widening of intracellular membrane structure were observed, and at age five months there were large vacuoles circumscribed by membranous lamellae, identifiable as myelin. Vacuoles in SAM-P/8 proved to be swollen neuronal processes and oligodendroglial processes. These SAM-P/8 and SAM-P/8/Ta strains of mice are new memory-deficient strains with spontaneous spongy degeneration associated with aging.

Animals↗
PubMed1998

The effects of different envelope patterns and uncertainty for the detection of a tone added to SAM complex tonal maskers.

Thresholds for the detection of a tone added in-phase to the carrier of a fully modulated SAM tone were measured. In some conditions the signal was added to a single SAM tone, and in other conditions the signal was added to the sum of three or more SAM tones. Level equalization ensured that the addition of the tonal signal did not lead to increases in energy. When multiple SAM tone maskers were used, a small number of reproducible maskers were tested, each masker being composed of SAM tones with a variety of relative modulator phases. The maskers were either fixed across intervals and trials, roved across trials but fixed across intervals, or randomly chosen across both intervals and trials. The frequency separation between the signal-centered and off-frequency SAM tones was also varied. For small signal-centered/off-frequency SAM tone frequency separations, a separation ratio of 1.3, thresholds in the fixed condition depend on the relative modulator phases, and a simple mixture model reasonably predicted thresholds in the roving condition based on thresholds in the fixed condition for two of the three observers. For signal-centered/off-frequency SAM tone frequency separation factor of 1.68, effects of relative modulator phases were not obtained. Thresholds in the target-alone condition were generally superior to thresholds measured with the comodulated masker. Comodulated thresholds were better than target-alone thresholds only when level equalization was not used, and so the addition of the signal led to increases in level.

Acoustic Stimulation↗
PubMed2005

Considerations when using the significance analysis of microarrays (SAM) algorithm.

BACKGROUND: Users of microarray technology typically strive to use universally acceptable data analysis strategies to determine significant expression changes in their experiments. One of the most frequently utilised methods for gene expression data analysis is SAM (significance analysis of microarrays). The impact of selection thresholds, on the output from SAM, may critically alter the conclusion of a study, yet this consideration has not been systematically evaluated in any publication. RESULTS: We have examined the effect of discrete data selection criteria (qualification criteria for inclusion) and response thresholds (out-put filtering) on the number of significant genes reported by SAM. The use of a reduced data set by applying arbitrary restrictions vis-à-vis abundance calls (e.g. from D-chip) or application of the fold change (FC) option within SAM (named the FC hurdle hereafter), can substantially alter the significant gene list when running SAM in Microsoft Excel. We determined that for a given final FC criteria (e.g. 1.5 fold change) the FC hurdle applied within Microsoft Excel SAM alters the number of reported genes above the final FC criteria. The reason is that the FC hurdle changes the composition of the control data set, such that a different significance level (q-value) is obtained for any given gene. This effect can be so large that it changes subsequent post hoc analysis interpretation, such as ontology overrepresentation analysis. CONCLUSION: Our results argue for caution when using SAM. All data sets analysed with SAM could be reanalysed taking into account the potential impact of the use of arbitrary thresholds to trim data sets before significance testing.

Adult↗
PubMed2006

Effects of neopterin on the hematopoietic microenvironment of senescence-accelerated mice (SAM).

The pteridine neopterin (NP) is produced by monocytes and is known to be a useful marker of immunological activation, although, it remains elusive whether neopterin itself exhibits biological functions. Recently, we found that NP stimulates hematopoietic cell proliferation and differentiation by activating bone marrow stromal cell function. In order to elucidate the biological effect of NP on stromal cells, its effects on hematopoiesis was determined in the mouse model of age-related stromal impairment, senescence-accelerated mice (SAMs). An intraperitoneal administration of NP increased the number of peripheral leukocytes and CFU-GM in the bone marrow and spleen of young SAMs, however, no increase of CFU-GM in old SAMs (stromal impairment) was observed when compared with young SAMs. NP also increased the CFU-GM colony formation of bone marrow and spleen cells from young SAMs in a soft agar culture system, but it did not enhance CFU-GM colony formation of cells from old SAMs cultured in this system. Treatment with NP induced the production of hematopoietic stimulating factors, including IL-6 and GM-CSF, by bone marrow stromal cells from young SAMs but stromal cells from old SAMs did not respond to NP stimulation. Further studies will be required to clarify the mechanism by which NP stimulates the production of hematopoietic growth factors from stromal cells, the results of this study indicate that NP is a potent hematopoietic regulatory factor by activating stromal cell function(s).

Aging↗