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PubMed2005

Managing the manganese: molecular mechanisms of manganese transport and homeostasis.

Manganese (Mn) is an essential metal nutrient for plants. Recently, some of the genes responsible for transition metal transport in plants have been identified; however, only relatively recently have Mn2+ transport pathways begun to be identified at the molecular level. These include transporters responsible for Mn accumulation into the cell and release from various organelles, and for active sequestration into endomembrane compartments, particularly the vacuole and the endoplasmic reticulum. Several transporter gene families have been implicated in Mn2+ transport, including cation/H+ antiporters, natural resistance-associated macrophage protein (Nramp) transporters, zinc-regulated transporter/iron-regulated transporter (ZRT/IRT1)-related protein (ZIP) transporters, the cation diffusion facilitator (CDF) transporter family, and P-type ATPases. The identification of mutants with altered Mn phenotypes can allow the identification of novel components in Mn homeostasis. In addition, the characterization of Mn hyperaccumulator plants can increase our understanding of how plants can adapt to excess Mn, and ultimately allow the identification of genes that confer this stress tolerance. The identification of genes responsible for Mn2+ transport has substantially improved our understanding of plant Mn homeostasis.

Biological Transport, Active↗
PubMed1992

Calcium homeostasis in pregnancy during long-term heparin treatment.

OBJECTIVE: To investigate the effect of subcutaneous heparin treatment on calcium homeostasis in pregnancy. DESIGN: A longitudinal case-control observational study. SETTING: Department of Obstetrics and Gynaecology, Karolinska Hospital, Stockholm, Sweden. SUBJECTS: 36 pregnant women with previously verified thromboembolic complications and 23 healthy pregnant control women similar in age, parity, weight, and smoking habit. INTERVENTIONS: Thromboprophylaxis during pregnancy and 6 weeks post partum was given with subcutaneous heparin twice daily to the 36 women with a history of thromboembolic complications, 16 received an average dose of 24,500 IU/day and 20 a mean dose of 17,300 IU/day. Venous blood and urine samples were obtained every 4 weeks. MAIN OUTCOME MEASURES: Serum concentrations of total calcium, ionized calcium, calcitonin and urinary calcium. RESULTS: Women on high-dose heparin treatment showed significantly higher concentrations of total and ionized calcium and of calcitonin in serum and significantly lower concentrations of calcium in urine than did 23 normal pregnant controls. The differences were most pronounced in the third trimester. The results obtained in the low-dose heparin group were between those in the high-dose and the control groups. At 8 weeks postpartum there were no significant differences between the heparin-treated women and the controls. No significant differences were found during pregnancy in haematocrit, liver or renal function, serum levels of albumin, phosphate, magnesium, alkaline phosphatase, parathyroid hormone or urinary cyclic AMP. CONCLUSIONS: Heparin treatment during pregnancy results in changes in calcium homeostasis and a dose-dependent response is suggested.

Adult↗
PubMed1990

Acid homeostasis following partial ischemia in neonatal brain measured in vivo by 31P and 1H nuclear magnetic resonance spectroscopy.

The purpose of this study was to investigate neonatal brain energy metabolism, acid, and lactate homeostasis in the period immediately following partial ischemia. Changes in brain buffering capacity were quantified by measuring mean intracellular brain pH, calculated from the chemical shift of Pi, in response to identical episodes of hypercarbia before and after ischemia. In addition, the relationship between brain buffer base deficit and intracellular pH was compared during and following ischemia. Thus, in vivo 31P and 1H nuclear magnetic resonance spectra were obtained from the brains of seven newborn piglets exposed to sequential episodes of hypercarbia, partial ischemia, and a second episode of hypercarbia in the postischemic recovery period. For the first episode of hypercarbia, brain buffering was similar to values reported for adult animals of other species (percentage pH regulation = 54 +/- 16%). During ischemia, the brain base deficit per unit change in pH was -19 +/- 5 mM/pH unit, which is similar to values reported for adult rats. By 20-35 min postischemia, brain acidosis partly resolved in spite of a net increase in lactate concentration. Therefore, the consumption of lactate could not explain acid homeostasis in the first 35 min following ischemia. We conclude that H+/HCO3- or other proton equivalent translocation mechanisms must be sufficiently developed in piglet brain to support acid regulation. This is surprising, because a substantial body of evidence implies these processes would be less active in immature brain. The second episode of hypercarbia, from 35 to 65 min postischemia, resulted in a smaller decrease in brain pH compared with the first episode, a result indicating an increase in brain buffering capacity (percentage pH regulation = 79 +/- 29%). This was associated with a parallel decrease in brain lactate content, and therefore acid regulation could be attributed to either continued ion translocation or the consumption of lactate. A mild decrease in brain pH and content of energy metabolites was observed, a finding suggesting that the metabolic consequences of severe postischemic hypercarbia are neither particularly dangerous or beneficial.

Acidosis, Respiratory↗
PubMed2005

The membrane-associated progesterone-binding protein 25-Dx is expressed in brain regions involved in water homeostasis and is up-regulated after traumatic brain injury.

After traumatic brain injury, progesterone has important neuroprotective effects in the nervous system. There is better functional outcome and less oedema formation in pseudopregnant rat females (high levels of endogenous progesterone) than in males. In addition to intracellular progesterone receptors, membrane binding sites of the hormone such as 25-Dx may also be involved in neuroprotection. In the present study we investigated the distribution of the membrane-associated progesterone-binding protein 25-Dx in rat brain. Immunohistochemical analysis showed that 25-Dx is particularly abundant in the hypothalamic area, circumventricular organs, and ependymal cells of the lateral walls of the third and lateral ventricles. A strong signal was also detected in the meninges. Double immunofluorescence immunolabelling and confocal microscopy showed that 25-Dx is co-expressed with vasopressin in neurones of the paraventricular, supraoptic and retrochiasmatic nuclei. Levels of 25-Dx expression were higher in pseudopregnant females than in males. After traumatic brain injury, 25-Dx expression was up-regulated in neurones and induced in astrocytes, which play an important role in regulating water and ion homeostasis. The expression of 25-Dx in structures involved in CSF production (choroid plexus) and in osmoregulation (circumventricular organs, hypothalamus and meninges), and its up-regulation after brain damage, point to a novel and potentially important role of this progesterone-binding protein in the maintenance of water homeostasis after traumatic brain injury.

Animals↗
PubMed2006

Gender differences in free radical homeostasis during aging: shorter-lived female C57BL6 mice have increased oxidative stress.

Gender is a profound determinant of aging and lifespan, but little is known about gender differences in free radical homeostasis. Free radicals are proposed as key elements in the multifactorial process of aging and it is predicted that the longer-lived gender should have lower levels of oxidative stress. While the majority of studies on aging have included a single gender, recent studies in rats compared genders and found that females, the longer-lived sex, had lower oxidative stress and mitochondrial dysfunction than males. We explored the association between oxidative stress and gender-specific aging in C57BL6 mice, in which females are the shorter-lived gender. Reactive oxygen species (ROS) were measured in young and old mice by confocal imaging of dihydroethidium (DHE) oxidation in the brain, and by electron paramagnetic resonance (EPR) spectrometry of isolated brain mitochondria. Both genders exhibited significant age-dependent increases in ROS. However, females had a greater increase with age than males in DHE oxidation but not mitochondrial EPR. Superoxide dismutase 1 (Sod1) and glutathione peroxidase 1 (GPx1) protein levels were lower in old females. To determine whether enhancing antioxidant defenses would eliminate gender differences in lifespan, mice were treated chronically with a superoxide dismutase mimetic. Treatment blocked the age-dependent increase in ROS, with a greater effect in females on DHE oxidation, but not mitochondrial EPR. Treatment also increased lifespan to a greater degree in females. Our results indicate that differences in ROS homeostasis contribute to gender divergence in survival, but also suggest that mitochondrial superoxide production may not be primarily responsible for gender differences in lifespan.

Aging↗
PubMed1996

The role of endogenous bradykinin in blood pressure homeostasis in spontaneously hypertensive rats.

1. The role of endogenous bradykinin in mean arterial blood pressure (BP) homeostasis was studied in spontaneously hypertensive (SHR) and normotensive (WKY) rats by the use of a bradykinin B2-receptor antagonist (BKant; Hoe 140, 11.6 micrograms kg-1) and converting enzyme (kininase II) inhibitor (captopril, 10 mg). To obtain a response to captopril that was induced through inhibition of kinin-degradation only and not through inhibition of angiotensin II-formation, the studies were performed on binephrectomized male rats to eliminate the renin-angiotensin system. 2. The role of the nitric oxide (NO) and the adrenergic systems were evaluated by the use of NO-synthase inhibitor (L-NAME, 0.3 g kg-1) and phentolamine (2 mg kg-1), respectively. 3. The rats were anaesthetized and pretreated with two injections of vehicle (PBS) or drugs spaced 5 min apart: PBS + PBS; BKant + PBS; PBS + L-NAME; BKant + L-NAME; or phentolamine + L-NAME. All rats were given captopril 15 min later. Time-control groups were treated with L-NAME but not captopril. 4. In WKY rats, captopril did not significantly alter BP in any of the groups. In the SHR-PBS + PBS group, on the other hand, captopril induced an immediate fall in BP (delta BP = -23 +/- 4 mmHg, P < 0.0017) which was completely blocked by BKant (delta BP = 2 +/- 2 mmHg) (P < 0.0011). L-NAME did not significantly alter the immediate hypotensive response to captopril but disclosed a later hypertensive reaction. In L-NAME + BKant-treated rats, both the hypotensive response and the late hypertension was abolished. In rats treated with phentolamine + L-NAME, the immediate fall in BP was not different from the controls whereas the late hypertension was absent. 5. BKant itself had no effect on basal BP in either WKY or SHR even when a 10 times higher dose was tested in a separate set of experiments. This was true also for conscious, nonnephrectomized SHR rats. 6. It was concluded that endogenous production of bradykinin was demonstrable through kininase II-inhibition in hypertensive but not in normotensive rats. However, this endogenous bradykinin did not play a role in basal BP homeostasis. The captopril-induced hypotension depended on kinin but, under the present conditions, not on NO as a mediator. The fall in BP induced a compensatory adrenergic hypertensive response which was revealed when the continuous NO-synthesis was blocked by L-NAME.

Animals↗
PubMedDate not supplied

Intracellular Ca2+ homeostasis in trypomastigotes of Trypanosoma cruzi.

Trypomastigotes of Trypanosoma cruzi maintain an intracellular Ca2+ concentration ([Ca2+]i) of 64 +/- 30 nM. Equilibration of trypomastigotes in an extracellular buffer containing 0.5 mM [Ca2+]o (preloaded cells) increased [Ca2+]i < 20 nM whereas total cell Ca2+ increased by 1.5 to 2.0 pmole/cell. This amount of Ca2+ would be expected to increase [Ca2+]i to > 10 microM suggesting active sequestration of Ca2+. We tested the hypothesis that maintenance of [Ca2+]i involved both the sequestration into intracellular storage sites and extrusion into the extracellular space. Pharmacological probes known to influence [Ca2+]i through well characterized pathways in higher eukaryotic cells were employed. [Ca2+]i responses in the presence or absence of [Ca2+]o were measured to asses the relative contribution of sequestration or extrusion processes in [Ca2+]i homeostasis. In the presence of 0.5 mM [Ca2+]o, the ability of several agents to increase [Ca2+]i was magnified in the order ionomycin >>> nigericin > thapsigargin > monensin > valinomycin. In contrast, preloading markedly enhanced the increase in [Ca2+]i observed only in response to monensin. Manoalide, an inhibitor of phospholipase A2, enhanced the accumulation of [Ca2+]i due to all agents tested, particularly ionomycin and thapsigargin. Our results suggest that sequestration of [Ca2+]i involved storage sites sensitive to monensin and ionomycin whereas extrusion of Ca2+ may involve phospholipase A2 activity. A Na+/Ca2+ exchange mechanism did not appear to contribute to Ca2+ homeostasis.

Animals↗
PubMed1990

pH homeostasis and bioenergetic work in alkalophiles.

A Na+/H+ antiporter catalyses coupled Na+ extrusion and H+ uptake across the membranes of extremely alkalophilic bacilli. This exchange is electrogenic, with H+ translocated inward greater than Na+ extruded. It is energized by the delta chi 2 component of the delta mu H+ that is established during primary proton pumping by the alkalophile respiratory chain complexes. These complexes abound in the membranes of extreme alkalophiles. Combined activity of the respiratory chain, the antiporter, and solute transport systems that are coupled to Na+ re-entry, allow the alkalophiles to maintain a cytoplasmic pH that is several pH units more acidic than optimal external pH values for growth. There is no compelling evidence for a specific and necessary role for any ion other than sodium in pH homeostasis, and although there is very high cytoplasmic buffering capacity in the alkaline range, active mechanisms for pH homeostasis are crucial. Energization of the antiporter as well as the proton translocating F1F0-ATPase that catalyses ATP synthesis in the extreme alkalophiles must accommodate the problem of the low net delta mu H+ and the very low concentrations of protons, per se, in the external medium. This problem is by-passed by other bioenergetic work functions, such as solute uptake or motility, that utilize sodium ions for energy-coupling in the place of protons.

Bacillus↗
PubMedDate not supplied

Inorganic phosphate homeostasis and the role of dietary phosphorus.

Inorganic phosphate (Pi) is required for cellular function and skeletal mineralization. Serum Pi level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, and renal tubular reabsorption. The crucial regulated step in Pi homeostasis is the transport of Pi across the renal proximal tubule. Type II sodium-dependent phosphate (Na/Pi) cotransporter (NPT2) is the major molecule in the renal proximal tubule and is regulated by Pi, parathyroid hormone and by 1,25-dihydroxyvitamin D. Recent studies of inherited and acquired hypophosphatemia [X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced rickets/osteomalacia (TIO)], which exhibit similar biochemical and clinical features, have led to the identification of novel genes, PHEX and FGF23, that play a role in the regulation of Pi homeostasis. The PHEX gene, which is mutated in XLH, encodes an endopeptidase, predominantly expressed in bone and teeth, but not in kidney. FGF-23 may be a substrate of this endopeptidase and may therefore accumulate in patients with XLH. In the case of ADHR mutations in the furin cleavage site, which prevent the processing of FGF-23 into fragments, lead to the accumulation of a "stable" circulating form of the peptide which also inhibits renal Pi reabsorption. In the case of TIO, ectopic overproduction of FGF-23 overwhelms its processing and degradation by PHEX, leading to the accumulation of FGF-23 in the circulation and inhibition of renal Pi reabsorption. Mice homozygous for severely hypomorphic alleles of the Klotho gene exhibit a syndrome resembling human aging, including atherosclerosis, osteoporosis, emphysema, and infertility. The KLOTHO locus is associated with human survival, defined as postnatal life expectancy, and longevity, defined as life expectancy after 75. In considering the relationship of klotho expression to the dietary Pi level, the klotho protein seemed to be negatively controlled by dietary Pi.

Animals↗
PubMed1995

Origins and functions of cells essential for periodontal repair: the role of fibroblasts in tissue homeostasis.

OBJECTIVE: A review is undertaken of rodent model systems and cell culture studies that address the role of periodontal fibroblasts in tissue homeostasis in both normal function and after wound healing. RATIONALE: Fibroblasts are the predominant cells of the periodontal ligament (PL) and of healthy gingiva and have important roles in the development, function and regeneration of the tooth support apparatus. REVIEW: In normally functioning periodontal tissues cell turnover involves generation of new cells by proliferation which in turn is balanced by apoptopic cell death. Consequently PL fibroblasts comprise a renewal cell system in steady-state. PL cell progenitors can generate multiple types of more differentiated, specialized cells including large numbers of fibroblastic cells and more limited numbers of osteogenic or cementogenic cells. However PL fibroblasts constitutively block osteogenesis and thereby maintain the PL width. Proliferating progenitor cell populations of the PL are enriched in locations adjacent to blood vessels and in contiguous endosteal spaces from where they migrate to the body of the PL. Large increases of cell formation and cell differentiation occur after wounding but surprisingly, the cells that repopulate the PL adjacent to the root surface are largely post-mitotic. As PL cell populations comprise multiple lineages, it is likely that after wounding, the separate phenotypes repopulating the wound site will be selected by environmental factors. Further, the specific repopulating lineages will strongly influence the form and function of the nascent tissue. To illustrate the specificity of fibroblast functions, examples of migratory and contractile fibroblast phenotypes are provided which exhibit constitutively different levels of gelsolin and alpha-smooth muscle actin respectively, cytoskeletal proteins which are markers for these cell types. CONCLUSION: Fibroblasts contribute to PL homeostasis by their abilities to remodel tissues, to repopulate wounds, to influence the metabolism of other cell types and to create a new fibrous attachment.

Animals↗
PubMed1988

Salt and water homeostasis during oral rehydration therapy in neonates and young infants with acute diarrhoea. II. Rehydration with a solution containing 90 mmol sodium per litre (ORS90).

The clinical response and changes in water and salt homeostasis were studied during oral rehydration therapy (ORT) with a solution containing 90 mmol sodium per 1 (ORS90) in 9 infants less than 2 months old (range 2-60 days). Two infants were still dehydrated 36 hours after starting ORT and were excluded from the study. Fluid was retained more rapidly and also to a larger extent than in infants of the same age treated with a solution with a sodium concentration of 60 mmol/l (ORS60). The stool sodium output was higher than that found previously in infants of the same age treated with ORS60. We conclude that during ORT the gut plays an active role in the regulation of salt homeostasis. When the sodium intake is high the percentage of sodium remaining unabsorbed is higher than when the intake is low. This mechanism reduces the risk of hypernatremia in young infants treated with ORS90. The study thus demonstrates that ORS90 is effective and also seems to be safe in the treatment of neonates and young infants with dehydration secondary to diarrhoea if fluid intake is kept around 200 ml/kg/day during the rehydration period.

Acute Disease↗
PubMed2005

Disruption of neuronal calcium homeostasis after chronic aluminium toxicity in rats.

The present study was designed to investigate the possible effects of chronic aluminium exposure on the various aspects of calcium homeostasis in rat brain. Chronic aluminium administration caused significant rise in the intrasynaptosomal calcium levels. The activity of major calcium-expelling enzyme, i.e. Ca2+ ATPase was found to be lowered. Also, the calcium uptake via voltage-operated calcium channels increased significantly. Similar to the increase in intrasynaptosomal calcium, calpain activity was found to be increased. The results presented here, indicate that the toxic effects of aluminium could be mediated through modifications in the intracellular calcium homeostasis, which may lead to impaired neuronal function.

Aluminum Compounds↗
PubMed1991

Potassium homeostasis during and following exhaustive submaximal static handgrip contractions.

The aim of the present study was to follow local potassium homeostasis during and after exhaustive contractions. Eight subjects performed static handgrip with their right forearm at 10%, 25% and 40% maximal voluntary contraction. Blood flow (venous occlusion plethysmography) and the venous effluent plasma potassium concentration were followed during the contractions and during a 60-min recovery period. Electromyography was registered during exercise (frequency analysis). With all three protocols the blood flow increased significantly during the contractions and the same was true of the effluent plasma potassium concentrations. In the recovery period blood flow and the venous effluent plasma potassium concentration returned to base values within 30 min following 40% maximal voluntary contraction while following 10% and 25% maximal voluntary contraction, venous effluent plasma potassium concentration was still significantly below resting values one hour after the exercise had ceased, indicating a long-lasting uptake of potassium from the blood into the muscles. In line with this a significant potassium deficit was still seen after 1 hour of recovery following 10% and 25% maximal voluntary contraction. It is concluded that the recovery of potassium homeostasis following prolonged low-intensity contractions is a slow process. This may be due to either sequestration of potassium in other tissues with a subsequent slow release and/or insufficient sodium/potassium pump activation. The contraction induced potassium loss may play a major role in muscle performance since it may impair mechanical force production, and it is hypothesized that this may be the origin of low-frequency fatigue.

Adult↗
PubMed1991

Change or homeostasis? A systems theory approach to depression.

Looking at the onset of depressive states in linear terms, there is often a problem of distinguishing cause and effect: did the adverse life-events cause the depression, or did the depression cause the adverse life-events? If we abandon linear thinking and look at depression in systemic terms, the problem of cause and effect disappears, but it is replaced by another problem: is the patient/environment system characterized by homeostasis or change? Some depressed patients seem to be spiralling down towards disaster. Others seem to be stuck in a rut. In systems terms, can depression be at the same time an agent of change and an agent of stasis (or even homeostasis)? The paradox can be resolved if we postulate that the function of depression is to reconcile the individual to an involuntarily subordinate social role; depression which reconciles to a pre-existing subordinate position has static properties; depression which mediates a switch to a subordinate position from a previously dominant position has properties of systemic change.

Depressive Disorder↗
PubMed2005

Heterogeneous chloride homeostasis and GABA responses in the median preoptic nucleus of the rat.

The median preoptic nucleus (MnPO) is an integrative structure of the hypothalamus receiving periphery-derived information pertinent to hydromineral and cardiovascular homeostasis. In this context, excitability of MnPO neurones is controlled by fast GABAergic, glutamatergic and angiotensinergic projection from the subfornical organ (SFO). Taking advantage of a brain slice preparation preserving synaptic connection between the SFO and the MnPO, and appropriate bicarbonate-free artificial cerebrospinal fluid (CSF), we investigated a possible implication of an active outward Cl- transport in regulating efficacy of the GABA(A) receptor-mediated inhibitory response at the SFO-MnPO synapse. When somata of the MnPO neurones was loaded with 18 mm chloride, stimulation of the SFO evoked outward inhibitory postsynaptic currents (IPSCs) in 81% of the MnPO neurones held at -60 mV. Accordingly, E(IPSC) was found 25 mV hyperpolarized from the theoretical value calculated from the Nernst equation, indicating that IPSC polarity and amplitude were driven by an active Cl- extrusion system in these neurones. E(IPSC) estimated with gramicidin-based perforated-patch recordings amounted -89.2 +/- 4.3 mV. Furosemide (100 microm), a pharmacological compound known to block the activity of the neurone-specific K(+)-Cl- cotransporter, KCC2, reversed IPSC polarity and shifted E(IPSC) towards its theoretical value. Presence of the KCC2 protein in the MnPO was further detected with immunohistochemistry, revealing a dense network of KCC2-positive intermingled fibres. In the presence of a GABA(B) receptor antagonist, high-frequency stimulation (5 Hz) of the SFO evoked a train of IPSCs or inhibitory postsynaptic potentials (IPSPs), whose amplitude was maintained throughout the sustained stimulation. Contrastingly, similar 5 Hz stimulation carried out in the presence of furosemide (50 microm) evoked IPSCs/IPSPs, whose amplitude collapsed during the high-frequency stimulation. Similar reduction in inhibitory neurotransmission was also observed in MnPO neurones lacking the functional Cl- extrusion mechanism. We conclude that a majority of MnPO neurones were characterized by a functional Cl- transporter that ensured an efficient activity-dependent Cl- transport rate, allowing sustained synaptic inhibition of these neurones. Pharmacological and anatomical data strongly suggested the involvement of KCC2, as an essential postsynaptic determinant of the inhibitory neurotransmission afferent to the MnPO, a key-structure in the physiology of the hydromineral and cardiovascular homeostasis.

Animals↗
PubMed1998

Plasma membrane depolarization and disturbed Na+ homeostasis induced by the protonophore carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazon in isolated nerve terminals.

The effect of the protonophore carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazon (FCCP) was studied on the intracellular [Na+], pH, and plasma membrane potential in isolated nerve terminals. FCCP induced a rise of [Na+]i at, and even below, the concentrations (0.025-1 microM) in which it is usually used in intact cells to eliminate Ca2+ uptake by mitochondria. The FCCP-induced increase of [Na+]i correlates with a fall in both the ATP level and the ATP/ADP ratio. In addition, a sudden rise of the intracellular proton concentration ([H+]i) from 83 +/- 0.4 to 124 +/- 0.7 nM was observed on the addition of FCCP (1 microM). Parallel with the rise in [H+]i, an abrupt depolarization was detected, followed by a slower decrease in the plasma membrane potential. Both the extent of the pHi change and the fast depolarization of the plasma membrane were proportional to the proton electrochemical gradient across the plasma membrane; when this gradient was increased, greater depolarization was detected. The slower decrease of the membrane potential after the fast initial depolarization was abolished when the medium contained no Na+. It is concluded that FCCP (1) gives rise to a depolarization by setting the plasma membrane potential close to the proton equilibrium potential and (2) enhances the intracellular [Na+] as a consequence of an insufficient ATP level and ATP/ADP ratio to fuel the Na+,K+/ATPase. Because both disturbed Na+ homeostasis and plasma membrane depolarization could profoundly interfere with Ca2+ homeostasis in the presence of protonophores, consideration given to these alterations may help to clarify the cellular Ca2+ sequestration processes.

Animals↗
PubMed2002

Pivalate-generating prodrugs and carnitine homeostasis in man.

Prodrugs that liberate pivalate (trimethylacetic acid) after hydrolysis have been developed to improve the bioavailability of therapeutic candidates. Catabolism of pivalate released by activation of a prodrug is limited in mammalian tissues. Pivalate can be activated to a coenzyme A thioester in cells. In humans, formation and urinary excretion of pivaloylcarnitine generated from pivaloyl-CoA is the major route of pivalate elimination. Because the total body carnitine pool is limited and can only slowly be replenished through normal diet or biosynthesis, treatment with large doses of pivalate prodrugs may deplete tissue carnitine content. Animal models and long-term treatment of patients with pivalate prodrugs have resulted in toxicity consistent with carnitine depletion. However, low plasma carnitine concentrations after pivalate prodrug exposure may not reflect tissue carnitine content and, thus, cannot be used as a surrogate for potential toxicity. The extent of tissue carnitine depletion will be dependent on the dose of pivalate, because carnitine losses may approximate the pivalate exposure on a stoichiometric basis. These concepts, combined with estimates of carnitine dietary intake and biosynthetic rates, can be used to estimate the impact of pivalate exposure on carnitine homeostasis. Thus, even in populations with altered carnitine homeostasis due to underlying conditions, the use of pivalate prodrugs for short periods of time is unlikely to result in clinically significant carnitine depletion. In contrast, long-term treatment with substantial doses of pivalate prodrugs may require administration of carnitine supplementation to avoid carnitine depletion.

Animals↗
PubMed2005

BZR1 is a transcriptional repressor with dual roles in brassinosteroid homeostasis and growth responses.

Brassinosteroid (BR) homeostasis and signaling are crucial for normal growth and development of plants. BR signaling through cell-surface receptor kinases and intracellular components leads to dephosphorylation and accumulation of the nuclear protein BZR1. How BR signaling regulates gene expression, however, remains unknown. Here we show that BZR1 is a transcriptional repressor that has a previously unknown DNA binding domain and binds directly to the promoters of feedback-regulated BR biosynthetic genes. Microarray analyses identified additional potential targets of BZR1 and illustrated, together with physiological studies, that BZR1 coordinates BR homeostasis and signaling by playing dual roles in regulating BR biosynthesis and downstream growth responses.

Arabidopsis↗