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PubMed1981

Insulin secretion in diabetes mellitus.

A brief review of the normal physiology of insulin secretion is given. The dual role of glucose to directly stimulate insulin release and to potentiate insulin secretion to other islet regulators is emphasized. The B cell of the pancreatic islet is discussed as a metabolic integrator for nutrients, modulated by neural and hormonal input. A feedback model for the normal regulation of glucose concentrations is also described. This model is based on a closed loop between the islet, the liver and peripheral tissues for the production and utilization of glucose. Diabetes mellitus with overt hyperglycemia is characterized by impaired pancreatic B-cell function; however, in noninsulin-dependent diabetic subjects, many aspects of insulin secretion are maintained by a compensatory increase in plasma glucose concentration. The model shows why this increase in plasma glucose occurs and the importance of this hyperglycemia to the restoration of insulin responses to nonglucose secretagogues, second-phase insulin secretion to glucose and basal insulin. The model can account for the usual stability of plasma glucose in noninsulin-dependent diabetes mellitus and the very high glucose levels and lack of glucose stability in insulin-dependent diabetes mellitus. Sulfonylurea drugs increase insulin secretion, but this increase is dependent on the glucose level. Thus, the augmented B-cell function can be masked by a decrease in plasma glucose concentrations. During long-term therapy, the insulin level and responses are unchanged despite lower concentrations of glucose. Therefore, it is hypothesized that sulfonylureas still act by enhancement of B-cell function.

Blood Glucose↗

PubMed1998

Glutamine synthetase expression in rat lung is regulated by protein stability.

During physiological stress, the lung increases production of the amino acid glutamine (Gln) using the enzyme Gln synthetase (GS) to maintain Gln homeostasis. Glucocorticoid hormones are considered the principal mediators of GS expression during stress. However, whereas animal studies have shown that glucocorticoids increase lung GS mRNA levels 500-700%, GS activity levels rise only 20-45%. This discrepancy suggests that a posttranscriptional control mechanism(s) ultimately determines GS expression. We hypothesized that the level of GS protein in the lung is governed by the intracellular Gln concentration through a mechanism of protein destabilization, a feedback regulatory mechanism that has been observed in vitro. To test this hypothesis, Sprague-Dawley rats were treated with a Gln-free diet and the GS inhibitor methionine sulfoximine (MSO) to deplete tissue Gln levels and prevent this feedback regulation. Exposure to Gln-free chow and MSO (100 mg/kg body wt) for 6 days decreased plasma Gln levels 50% (P < 0.01) and decreased lung tissue Gln levels by 70% (P < 0.01). Although lung GS mRNA levels were not influenced by Gln depletion, there was a sevenfold (P < 0.01) increase in GS protein. A parenteral Gln infusion (200 mM, 1.5 ml/h) for the last 2 days of MSO treatment replenished lung Gln levels to 65% of control level and blunted the increase in GS protein levels by 33% (P < 0.05) compared with rats receiving an isomolar glycine solution. The acute effects of glucocorticoid and MSO administration on lung GS expression were also measured. Whereas dexamethasone (0.5 mg/kg) and MSO injections individually augmented lung GS protein levels twofold and fourfold (P < 0.05), respectively, the combination of dexamethasone and MSO produced a synergistic, 12-fold induction (P < 0.01) in lung GS protein over 8 h. The data suggest that, whereas glucocorticoids are potent mediators of GS transcriptional activity, protein stability greatly influences the ultimate expression of GS in the lung.

Animals↗

PubMed2004

IL-4 induces production of the lung collectin surfactant protein-D.

BACKGROUND: Surfactant protein (SP)-D is an epithelial cell product of the distal air spaces that aids uptake and clearance of inhaled pathogens and allergens. Allergic airway inflammation significantly increases SP-D levels in the bronchoalveolar lavage fluid in asthmatic patients and mouse models, but the mechanisms involved remain unknown. OBJECTIVE: To investigate the effects of the TH2-type cytokine IL-4 on SP-D production by isolated pulmonary epithelial cells. METHODS: Rat type II alveolar epithelial cells were purified and cultured with dexamethasone, cAMP, and isobutyl-1-methylxanthine (DCI). The effects of IL-4 on SP-D expression were investigated at the protein and mRNA levels by means of Western and Northern blot analyses. RESULTS: In contrast to a lamellar body protein ABCA3 and surfactant protein-A, expression of SP-D significantly declined when cells were cultured in medium alone for 24 hours. The presence of DCI in the culture medium restored SP-D levels, which were enhanced by 2-fold after addition of recombinant IL-4. The enhancing effects of IL-4 were concentration-dependent, with maximum effects observed at 20 ng/mL (1.43 nmol/L). IL-4 did not rescue cycloheximide-induced decrease of intracellular SP-D levels and did not inhibit extracellular release of SP-D. However, IL-4 significantly augmented DCI-induced SP-D mRNA expression by approximately 2.5-fold over control levels. CONCLUSIONS: IL-4 selectively upregulates SP-D expression, and it may act at the level of mRNA in isolated pulmonary epithelial cells. Since SP-D has a potent anti-inflammatory function, this mechanism may be part of a negative feedback loop providing a regulatory link between adaptive and innate immunity during allergic inflammation.

1-Methyl-3-isobutylxanthine↗

PubMed1994

Control of breathing patterns and abdominal muscles during graded loads and tilt.

Tilting from supine to upright purportedly enhances both segmental and pulmonary proprioceptive feedback, whereas an expiratory threshold load (ETL) preferentially enhances pulmonary feedback. To test this we studied 13 adults when supine and 60 degrees and 90 degrees head up. We measured tidal volume, inspiratory duration (TI), and expiratory duration (TE) from flow; estimated end-expiratory lung volume from inspiratory capacity; and determined burst amplitudes and durations from abdominal electromyograms (EMGs). ETLs were incremented from 0 (control) to 25 cmH2O in 5-cmH2O steps. Tidal volume was significantly increased by ETL but was unaffected by body position. Every load prolonged TE, whereas TI remained unchanged. When subjects were supine, abdominal EMGs were silent but became tonically active when subjects were upright. During ETL, abdominal activity became rhythmical and phase locked to expiration. Bursts amplitudes were enhanced with each increment in ETL, but burst durations did not change even though TE was prolonged. The altered breathing pattern and active expiration augmented inspiratory flow and decreased end-tidal PCO2. Responses were greatest when subjects were 90 degrees head up. The load-related increments in abdominal recruitment, with no change in burst durations, fit the concept of two central pattern generators: one controlling pattern and the other controlling rhythm of the central respiratory drive.

Abdominal Muscles↗

PubMed1991

Tubuloglomerular feedback activity after acute reductions in renal mass.

Removal of one kidney results in prompt increases in urinary excretion of NaCl and water from the remaining kidney, followed rather soon thereafter by increases in glomerular filtration rate (GFR). At 12-15 h and 24 h after contralateral nephrectomy, the single nephron filtration rate (SNGFR) is increased, accompanied by parallel increases in absolute proximal tubular reabsorption, late proximal tubular and early distal tubular flow rates, suggesting that these events might be critical to the increased urinary excretion. However, micropuncture studies 2-4 h after contralateral nephrectomy demonstrate that increased SNGFR and even increased distal tubular flow rates are not requirements for augmented urinary excretion, suggesting that decreased tubular reabsorption in the most distal nephron segments causes the increase in urinary excretion. Analysis of TGF profiles by stop-flow pressure response at 2-4 h after contralateral nephrectomy have suggested suppression of TGF as assessed by a rightward shift in the turning point with increasing late proximal tubular perfusion. However, our studies have examined SNGFR responses and shown no suppression of TGF profiles but a downward shift in the operating point, suggesting activation of TGF and a modest reduction in SNGFR, determined from distal tubular collections. Although SNGFR was increased at all late proximal perfusion rates 12 h after nephrectomy, the turning point (V 1/2) was not altered. TGF profiles are not suppressed within 12 h after nephrectomy while SNGFR is increased. Suppression of TGF does not cause the increase in SNGFR after nephrectomy and TGF activity is maintained and adapts to increases in SNGFR caused by TGF-independent mechanisms.

Animals↗

PubMed1987

Chronic morphine treatment enhances the negative and positive feedback effects of estradiol on gonadotropin secretion in ovariectomized rats.

Studies were undertaken to evaluate the effects of chronic morphine exposure on the negative and positive feedback effects of estradiol (E2) on LH and FSH secretion in ovariectomized rats. Two days of E2 exposure reduced at 1000 h and stimulated at 1600 h the serum LH concentration at each dose tested. Chronic exposure (4 days) to morphine enhanced both the inhibitory effects of E2 on LH secretion at 1000 h and E2 induction of the midafternoon surge in LH. A detailed time course of the afternoon LH response to E2 revealed that chronic morphine exposure advanced its time of onset and increased its magnitude. The response of FSH to E2 and the interaction between E2 and morphine on FSH secretion were similar to those observed for LH, albeit lower in magnitude. With extension of the E2 exposure period from 2 to 4 days, the synergistic interaction between E2 and morphine persisted for the negative, but not the positive, feedback action on LH. Chronic morphine exposure in ovariectomized rats, without E2 replacement, was ineffective in altering the LH levels at 1000 h, but had a slight stimulatory effect on LH at 1600 h, indicating an E2 requirement for the observed suppression and stimulation of LH in the morning and afternoon, respectively. The response of the anterior pituitary to exogenously administered LHRH in the morning (1000 h) and during the midafternoon hypersecretion of LH (1800 h) was markedly enhanced in animals exposed chronically to morphine. Thus, the chronic stimulation of opiate receptors with morphine enhances the inhibition and subsequent hypersecretion of LH in E2-exposed rats, advances the time of onset and enhances the magnitude of the E2-induced LH surge, and augments the response to LHRH when LH levels are low in the morning and during the E2-induced hypersecretion of LH. These data support an important role for opioid neuronal systems in the mechanism that switches the E2 signal for gonadotropin secretion from inhibitory to stimulatory and, hence, in the series of neuronal events that leads to phasic secretion of gonadotropins.

Animals↗

PubMed2003

Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis.

Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InsP(3)R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP(3)R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InsP(3)R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP(3)R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP(3)R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.

Animals↗

PubMed2003

Use of the orthogonal projection approach (OPA) to monitor batch processes.

The orthogonal projection approach (OPA) and multivariate curve resolution (MCR) are presented as a way to monitor batch processes using spectroscopic data. Curve resolution allows one to look within a batch and predict on-line real concentration profiles of the different species appearing during reactions. Taking into account the variations of the process by using an augmented matrix of complete batches, the procedure explained here calculates some prediction coefficients that can afterwards be applied for a new batch.

Algorithms↗

PubMed1980

[The effect of glucose and 2-deoxy-D-glucose on the monodeiodination of thyroxine by human skin fibroblasts in culture (author's transl)].

The effect of glucose and 2-deoxy-D-glucose on the extrathyroidal monodeiodination of thyroxine (T4) to 3, 5, 3'-triiodothyronine (T3) and 3, 3', 5'-triiodohyronine (reverse T3;rT3) was studied in human skin fibroblasts in culture. When the fibroblasts were maintained in glucose-free Eagle's MEM fortified with 3% fetal calf serum, intracellular T4 was unchanged, intracellular T3 decreased, and intracellular rT3 markedly increased as compared with those in Eagle's MEM containing 3% fetal calf serum and 100 mg/dl glucose. In this study, the ratio of T3 to T4 fell, and the ratio of rT3 to T4 and rT3 to T3 rose remarkably in fibroblasts in glucose-deprived media. When the fibroblasts were maintained in Eagle's MEM containing 3% fetal calf serum and various concentration of 2-deoxy-D-glucose, intracellular concentrations of thyroid hormone were decreased as compared with those in 2-deoxy-D-glucose-free control medium. The ratio of rT3 to T4 and rT3 to T3, however, augmented although the ratio of T3 to T4 did not change in fibroblasts in the media with 2-deoxy-D-glucose. Cellular energetic deprivation derived from the glucose-free medium and the medium containing 2-deoxy-D-glucose influenced the extrathyroidal monodeiodination of T4 by shifting from T3 to rT3 or vice versa, in addition to the feedback system of the pituitary-thyroidal exis.

Culture Techniques↗

PubMed2001

Neurophysiological regulation and target-tissue impact of the pulsatile mode of growth hormone secretion in the human.

Neuroendocrine axes function as an ensemble of regulatory loci which communicate and maintain homeostasis via time-delayed blood-borne signals. The growth hormone (GH)-insulin-like growth factor I (IGF-I) feedback axis sustains a vividly pulsatile mode of interglandular signalling. Pulsatility is driven jointly by hypothalamic GH-releasing hormone (GHRH) and GH-releasing peptide (GHRP), and modulated by somatostatinergic restraint. Paradoxically, intermittent somatostatin inputs also facilitate somatotrope-cell responses to recurrent secretagogue stimuli, thereby amplifying pulsatile GH secretion. A concurrent low basal (8-12% of normal total) rate of GH release is controlled positively by GHRH and GHRP and negatively by somatostatin. Sex-steroid hormones (such as oestradiol and aromatizable androgen) and normal female and male puberty augment GH secretory-burst mass 1.8- to 3.5-fold, whereas ageing, relative obesity, physical inactivity, hypogonadism, and hypopituitarism mute the amplitude/mass of pulsatile GH output. An abrupt rise in circulating GH concentration stimulates rapid internalization of the GH receptor in peripheral target tissues, and evokes second-messenger nuclear signalling via the STAT 5b pathway. Discrete GH peaks stimulate linear (skeletal) growth and drive muscle IGF-I gene expression more effectually than basal (time-invariant) GH exposure. A brief pulse of GH can saturate the plasma GH-binding protein system and achieve prolonged plasma GH concentrations by convolution with peripheral distribution and clearance mechanisms. A single burst of GH secretion also feeds back after a short latency on central nervous system (CNS) regulatory centres via specific brain GH receptors to activate somatostatinergic and reciprocally subdue GHRH outflow. This autoregulatory loop probably contributes to the time-dependent physiologically pulsatile dynamics of the GH axis. More slowly varying systemic IGF-I concentrations may also damp GH secretory pulse amplitude by delayed negative-feedback actions. According to this simplified construct, GH pulsatility emerges due to time-ordered multivalent interfaces among GHRH/GHRP feedforward and somatostatin, GH and IGF-I feedback signals. Resultant GH pulses trigger tissue-specific gene expression, thereby promoting skeletal and muscular growth, metabolic and body compositional adaptations, and CNS reactions that jointly maintain health and homeostasis.

Aging↗

PubMed2003

Membrane-bound form of fractalkine induces IFN-gamma production by NK cells.

Natural killer (NK) cells participate in both innate and adaptive immunity, in part by their prompt secretion of cytokines including IFN-gamma, a pro-inflammatory cytokine with an important role in Th1 polarization. To assess the involvement of fractalkine in inflammatory processes, we examined the effect of fractalkine on IFN-gamma production by NK cells. Although soluble chemokines, including MCP-1 and RANTES as well as fractalkine, had a negligible effect on IFN-gamma production, immobilized fractalkine markedly induced IFN-gamma production by NK cells in a dose-dependent manner. Pretreatment of NK cells with the phosphatidylinositol 3-kinase (PI 3-K) inhibitor, wortmannin, completely inhibited the production of IFN-gamma induced by fractalkine, and pretreatment with the protein tyrosine kinase inhibitor, herbimycin A, partially suppressed the response, suggesting that augmentation of IFN-gamma production in response to fractalkine treatment of NK cells involves signaling through PI 3-K and protein tyrosine kinases. Furthermore, co-culture of NK cells with fractalkine-transfected 293E cells markedly enhanced IFN-gamma production by NK cells compared with co-culture with control 293E cells. These findings may indicate a paracrine feedback loop system in which endothelial cells may be activated to produce more fractalkine, and also suggest a role for fractalkine expressed on endothelial cells in Th1 polarization through the stimulation of IFN-gamma production by NK cells.

Cell Division↗

PubMed1977

Inking in Aplysia californica. III. Two different synaptic conductance mechanisms for triggering central program for inking.

1. In the previous two papers we described the motor elements which mediate all-or-none inking behavior in Aplysia (4) and the contribution of specific membrane properties of the ink-gland motor cells to the central program for inking (5). In the present paper we show that the central program for inking (a characteristic accelerating burst of action potentials in the motor cells) can be triggered in two different ways: 1) by means of a suprathreshold stimulus delivered to a single site on the animal; and 2) by means of two subthreshold stimuli closely spaced in time, delivered either to the same or to different sites on the animal. 2. The single suprathreshold stimulus triggers the central program primarily by means of a complex increased-conductance EPSP. The two subthreshold stimuli trigger the program by means of a complex decreased-conductance EPSP which is capable of augmenting subsequent afferent synaptic input. 3. The synaptic augmentation produced by the decreased-conductance EPSP is attributable to two properties of the EPSP: 1) it increases the input resistance of the ink-gland motor cells so that the synaptic current from afferent input onto the cells produces larger, more effective EPSP's; and 2) it increases the electrotonic coupling among the motor cells, thereby producing increased positive feedback among them. Thus, the decreased-conductance EPSP provides a novel mechanism for spatial and temporal summation.

Animals↗

PubMed2005

Balance between NF-kappaB and JNK/AP-1 activity controls dendritic cell life and death.

The life cycle of dendritic cells (DCs) must be precisely regulated for proper functioning of adaptive immunity. However, signaling pathways actively mediating DC death remain enigmatic. Here we describe a novel mechanism of hierarchical transcriptional control of DC life and death. Ligation of tumor necrosis factor receptor superfamily (TNFR-SF) members on DCs and cognate contact with T cells resulted in quantitatively balanced nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)-mediated activator protein-1 (AP-1) induction and strongly enhanced DC longevity. Specific blockade of NF-kappaB in DCs induced strongly augmented JNK/AP-1 activity because of elevated levels of reactive oxygen species. In this scenario, DC activation by TNFR-SF members or T cells induced DC apoptosis. Specific inhibition of JNK/AP-1 rescued DCs from this activation-induced cell death program and restored TNFR-SF member- and T-cell-mediated survival. We conclude that JNK/AP-1 activity is under negative feedback control of NF-kappaB and can execute apoptosis in DCs. Thus, feedback-controlled signaling amplitudes of 2 transcriptional pathways decide the fate of a DC.

CD40 Antigens↗

PubMed1980

Luteinizing hormone releasing factor in pituitary stalk plasma from long-term ovariectomized rats: effects of steroids.

The concentration of LH releasing factor (LH-RF) was measured by radioimmunoassay in blood collected from the cut pituitary stalk of long-term ovariectomized rats anaesthetized with Althesin. Stalk plasma LH-RF concentrations were increased immediately after ovariectomy (carried out at oestrus) and low at 2 and 4 days after operation. The concentrations then began to increase to reach a level at 24-28 days which was significantly higher than the concentrations during the oestrous cycle except for the time of the ovulatory surge at pro-oestrus. This pattern was similar to that of the concentrations of LH in jugular venous plasma taken from the same animals before exposure of the pituitary stalk. Like peripheral plasma LH concentrations, the concentrations of LH-RF in stalk plasma fluctuated and fell significantly and rapidly after the intravenous injection of 1 microgram oestradiol-17 beta. The release of LH-RF in long-term ovariectomized rats, into which had been implanted an oestradiol-containing Silastic capsule, was similar to the diurnal pattern of LH release; the afternoon increase in stalk plasma LH-RF concentration could be blocked by sodium pentobarbitone administered at 13.00 h and augmented by administering this anaesthetic at 13.00 h of the preceding day. The stalk plasma LH-RF concentrations in animals injected with oestradiol benzoate (OB) followed 72 h later with either OB or progesterone were lower than the concentrations in animals injected only with oil. These data show that in the rat (1) ovarian steroids could moderate LH release ('negative feedback') by inhibiting LH-RF release, and that in long-term ovariectomized animals (2) the oestradiol-induced circadian pattern of LH release is due to a circadian pattern of LH-RF release, and (3) the surge of LH produced by administering OB followed by either OB or progesterone is probably due mainly to a massive increase in the responsiveness of the anterior pituitary gland to LH-RF.

Animals↗

PubMed2005

Short-interfering RNA-mediated Lck knockdown results in augmented downstream T cell responses.

The Src family kinase Lck is essential for T cell Ag receptor-mediated signaling. In this study, we report the effects of acute elimination of Lck in Jurkat TAg and primary T cells using RNA interference mediated by short-interfering RNAs. In cells with Lck knockdown (kd), proximal TCR signaling was strongly suppressed as indicated by reduced zeta-chain phosphorylation and intracellular calcium mobilization. However, we observed sustained and elevated phosphorylation of ERK1/2 in Lck kd cells 30 min to 2 h after stimulation. Downstream effects on immune function as determined by activation of a NFAT-AP-1 reporter, and TCR/CD28-stimulated IL-2 secretion were strongly augmented in Jurkat and primary T cells, respectively. As expected, overexpression of SHP-1 in Jurkat cells inhibited TCR-induced NFAT-AP-1 activation, but this effect could be overcome by simultaneous kd of Lck. Furthermore, acute elimination of Lck also suppressed TCR-mediated activation of SHP-1, suggesting the possible role of SHP-1 in a negative feedback loop originating from Lck. This report underscores Lck as an important mediator of proximal TCR signaling, but also indicates a suppressive role on downstream immune function.

Blotting, Northern↗

PubMed2003

Chloride channel blockade attenuates the effect of angiotensin II on tubuloglomerular feedback in WKY but not spontaneously hypertensive rats.

Recent studies have shown that calcium-dependent chloride channels may play a crucial role in the modulation of the vascular effects of angiotensin II (ANG II). Thus, alterations in the function of these channels may be responsible for the enhanced renal vasoconstrictor and tubuloglomerular feedback (TGF) response to ANG II in spontaneously hypertensive rats (SHR). We investigated the effect of the calcium-dependent chloride channel blocker IAA-94 on renal hemodynamics and TGF responses. The renal interstitium was perfused with control solution, with ANG II, and with both ANG II and IAA-94. In Wistar Kyoto rats (WKY), perfusion with ANG II significantly increased renal vascular resistance (RVR), but the effect was significantly attenuated by perfusion with ANG II/IAA-94. In SHR, ANG II caused a significant elevation of RVR that was not altered by the simultaneous infusion of IAA-94. Proximal tubular stop flow pressure (P(sf)) was monitored during perfusion of peritubular capillaries with control solution, and subsequently with IAA-94, ANG II or both ANG II and IAA-94. TGF response magnitude of WKY rats was significantly augmented with ANG II, and this effect was suppressed by perfusion with ANG II /IAA-94. However, in SHR peritubular perfusion with ANG II/IAA-94 did not suppress the TGF response. We conclude that chloride channels susceptible to IAA-94 may play a significant role in modulating the effects of ANG II on renal hemodynamics, and that this modulation is absent in SHR.

Angiotensin II↗

PubMed1996

Peripheral control of the gain of a central synaptic connection between antagonistic motor neurones in the locust

The metathoracic fast extensor tibiae (FETi) motor neurone of locusts is unusual amongst insect motor neurones because it makes output connections within the central nervous system as well as in the periphery. It makes excitatory chemical synaptic connections to most if not all of the antagonist flexor tibiae motor neurones. The gain of the FETi-flexor connection is dependent on the peripheral conditions at the time of the FETi spike. This dependency has two aspects. First, sensory input resulting from the extensor muscle contraction can sum with the central excitatory postsynaptic potential (EPSP) to augment its falling phase if the tibia is restrained in the flexed position (initiating a tension-dependent reflex) or is free to extend (initiating a movement-dependent resistance reflex). This effect is thus due to simple postsynaptic summation of the central EPSP with peripheral sensory input. Second, the static tibial position at the time of the FETi spike can change the amplitude of the central EPSP, in the absence of any extensor muscle contraction. The EPSP can be up to 30 % greater in amplitude if FETi spikes with the tibia held flexed rather than extended. The primary sense organ mediating this effect is the femoral chordotonal organ. Evidence is presented suggesting that the mechanism underlying this change in gain may be specifically localised to the FETi-flexor connection, rather than being due to general position-dependent sensory feedback summing with the EPSP. The change in the amplitude of the central EPSP is probably not caused by general postsynaptic summation with tonic sensory input, since a diminution in the amplitude of the central EPSP caused by tibial extension is often accompanied by overall tonic excitation of the flexor motor neurone. Small but significant changes in the peak amplitude of the FETi spike have a positive correlation with changes in the EPSP amplitude, suggesting a likely presynaptic component to the mechanism of gain control. The change in amplitude of the EPSP can alter its effectiveness in producing flexor motor output and, thus, has functional significance. The change serves to augment the effectiveness of the FETi-flexor connection when the tibia is fully flexed, and thus to increase its adaptive advantage during the co-contraction preceding a jump or kick, and to reduce the effectiveness of the connection when the tibia is partially or fully extended, and thus to reduce its potentially maladaptive consequences during voluntary extension movements such as thrusting.

Journal Article↗

PubMed2006

Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling.

Sphingosine 1-phosphate (S1P), produced by sphingosine kinase (SPHK), acts both by intracellular and extracellular modes. We evaluated the role of SPHK1 and S1P in osteoclastogenesis using bone marrow-derived macrophage (BMM) single and BMM/osteoblast coculture systems. In BMM single cultures, the osteoclastogenic factor receptor activator of NF-kappaB ligand (RANKL) upregulated SPHK1 and increased S1P production and secretion. SPHK1 siRNA enhanced and SPHK1 overexpression attenuated osteoclastogenesis via modulation of p38 and ERK activities, and NFATc1 and c-Fos levels. Extracellular S1P had no effect in these cultures. These data suggest that intracellular S1P produced in response to RANKL forms a negative feedback loop in BMM single cultures. In contrast, S1P addition to BMM/osteoblast cocultures greatly increased osteoclastogenesis by increasing RANKL in osteoblasts via cyclooxygenase-2 and PGE(2) regulation. S1P also stimulated osteoblast migration and survival. The RANKL elevation and chemotactic effects were also observed with T cells. These results indicate that secreted S1P attracts and acts on osteoblasts and T cells to augment osteoclastogenesis. Taken together, S1P plays an important role in osteoclastogenesis regulation and in communication between osteoclasts and osteoblasts or T cells.

Animals↗