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PubMed1994

Compartmentalized immune response reflects clinical severity of beryllium disease.

Although beryllium disease has been associated with a bronchoalveolar lavage (BAL) lymphocytosis and T cell-mediated immune response, we do not know if either the BAL cellular profile or the compartmentalized pulmonary response to the antigen reflect the severity of the disease. We studied 110 subjects divided into three groups of subjects: beryllium disease patients (n = 55), beryllium-sensitized patients without disease (n = 8), and control subjects (n = 47). Evaluation included completion of a respiratory symptom questionnaire, clinical examination, chest radiograph, spirometry, body plethysmographic lung volumes, and diffusing capacity (DLCO). In the patient groups, we performed maximal exercise testing with an indwelling arterial line. In addition, we examined BAL and performed blood and BAL beryllium lymphocyte transformation tests (BeLT) as measures of the beryllium-specific T cell-mediated response in these two compartments. In beryllium disease patients we correlated the BAL cellular constituents with clinical parameters indicative of disease severity. Beryllium disease patients exhibited elevated numbers of white cells and lymphocytes in BAL compared with both other groups; however, this lymphocytic alveolitis was significantly obscured in smokers. The BAL cellular constituents correlated with BAL BeLT but not with the blood BeLT. BAL cellular constituents also correlated with the radiographic profusion of small opacities, FEV1/FVC, DLCO, maximal achievable work load, VO2max, and measures of gas exchange at rest and at maximum exercise. We conclude that the lymphocyte-predominant pulmonary inflammatory response in beryllium disease is related to the magnitude of the localized response to antigen and that BAL cellularity, differential cell count, and BeLT reflect beryllium disease clinical severity.(ABSTRACT TRUNCATED AT 250 WORDS)

Berylliosis↗
PubMed1999

Compartmentalization of the inflammatory response to inhaled grain dust.

Interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and the secreted form of the IL-1 receptor antagonist (sIL-1RA) are involved in the inflammatory response to inhaled grain dust. Previously, we found considerable production of these cytokines in the lower respiratory tract of workers exposed by inhalation to aqueous extracts of corn dust extract. Alveolar macrophages (AM) have long been considered the cell type responsible for producing these cytokines, and only recently has it been realized that airway epithelial cells may also be involved in cytokine production. In order to determine whether airway epithelia are involved in the inflammatory response to inhaled corn dust extract and to compare the magnitude of response of bronchial epithelial cells (BE) and bronchoalveolar lavage (BAL) cells, we used the reverse transcriptase/polymerase chain reaction (RT/PCR) technique in a semiquantitative manner to evaluate the concentration of IL-1beta, IL-6, IL-8, TNF-alpha, and sIL-1RA. Alveolar cells were obtained by BAL, and BE were obtained by endobronchial brush biopsy from 15 grain handlers 6 h after experimental inhalation of saline or an aqueous corn dust extract. After inhalation of saline, BE expressed low but detectable levels of IL-6, IL-8, and IL-1beta (> 1 complementary DNA [cDNA] molecule/cell). After inhalation of corn dust extract, the expression of messenger RNA (mRNA) for IL-1beta and IL-8 in the BE were significantly increased, whereas no change was seen in IL-6, sIL-1RA, and TNF-alpha mRNA expression. Comparing cytokine mRNA levels in BE and BAL cells from the same subjects after inhalation of corn dust extract, BE and BAL cells expressed equivalent amounts of IL-8 mRNA; IL-1beta was 11-fold higher in BAL cells; and TNF-alpha and sIL-1RA were expressed exclusively by BAL cells. Immunostaining for the cytokines in BAL cells showed cytokine protein expression in AMs but not in polymorphonuclear cells (PMNs). On the other hand, sIL-1RA was strongly expressed in both AMs and PMNs. Analysis of cytokine protein levels in endobronchial lavage (EBL) fluid demonstrated that only IL-8 was released in detectable amounts into the airway lumen, whereas all the other cytokines of interest were exclusively found in the BAL fluid. Thus, within 6 h after inhalation exposure to corn dust extract, BE appear to contribute to airway inflammation by producing IL-8. AMs are responsible for most of the IL-1beta and IL-6 production in the alveolar region, whereas AMs and PMNs both produce sIL-1RA. Our findings suggest that the inflammatory response to inhaled grain dust is compartmentalized, involving specific mediators of inflammation released by macrophages, neutrophils, and airway epithelial cells.

Adolescent↗
PubMed1984

Accuracy of respiratory inductive plethysmograph over wide range of rib cage and abdominal compartmental contributions to tidal volume in normal subjects and in patients with chronic obstructive pulmonary disease.

We assessed the accuracy of the respiratory inductive plethysmograph in the supine position to spirometry by the two-body position, least squares calibration and single-body position, isovolume calibration procedures. The comparison was carried out simultaneously in normal subjects breathing naturally and with voluntarily controlled abdominal or thoracic breathing, and in patients with COPD breathing naturally and with voluntarily controlled abdominal breathing patterns. In both groups, there was no significant difference in estimation of tidal volume between the 2 calibration procedures for the various breathing patterns. There was greater deviation from spirometric tidal volume values for both calibration methods in patients with COPD during abdominal than during natural breathing. In the normal subjects, agreement between the rib cage and abdominal partitioning of tidal volume for both calibration methods was good, but in the patients with COPD there was greater variability. In normal subjects, over a wide range of rib cage and abdominal compartmental contributions to tidal volume, either calibration procedure appears satisfactory. For patients with COPD, if large changes occur in the distribution of rib cage and abdominal contributions to tidal volume, then validation of respiratory inductive plethysmography to spirometry must be rechecked.

Abdomen↗
PubMed1987

Natural killer cell function in human lung is compartmentalized.

Natural killer (NK) cells are a subpopulation of lymphocytes capable of killing a variety of neoplastic targets. NK can limit pulmonary metastases in animal models and could be important mediators of tumor defense in human lung. Previous studies in humans have suggested, however, that pulmonary NK cells obtained by bronchoalveolar lavage (BAL) are functionally inert. We purified lymphocytes from human lung tissue and compared the NK activity of these cells with lymphocytes purified from peripheral blood. The activity of NK cells obtained from minced whole lung specimens was comparable to that found in peripheral blood. Monoclonal antibodies to 2 markers found on peripheral blood large granular lymphocytes (LGL) were utilized to determine the phenotype of pulmonary NK cells. Lymphocytes expressing Leu 11b were responsible for pulmonary NK activity as all NK function was abrogated by pretreatment with anti-Leu 11b and complement. In contrast, lymphocytes expressing Leu 7 had little NK activity. Although the frequency of lymphocytes expressing Leu 7 or Leu 11 in blood was comparable, there were significantly more (p less than 0.001) Leu 7+ lymphocytes in the lung than Leu 11+ cells. Immunofluorescent staining of lung tissue demonstrated that LGL expressing Leu 11 were confined largely to the lung interstitium, whereas LGL expressing Leu 7 were frequently located in alveoli and larger airways. These findings suggest that NK function is present in the human lung and that it is compartmentalized with the NK-active Leu 11+ lymphocytes located primarily in the lung interstitium.

Adult↗
PubMed2003

Lipid raft compartmentalization of urokinase receptor signaling in human neutrophils.

Urokinase plasminogen activator (uPA) receptors (uPAR) can be engaged for activation signaling either by aggregation or by binding exogenous uPA. These signaling mechanisms require uPAR to associate with two distinct adhesion proteins, L-selectin and complement receptor 3 (CR3), respectively. uPAR contains a glycosylphosphatidylinositol anchor, suggesting that it is concentrated within glycosphingolipid-enriched microdomains, or "lipid rafts". This study was undertaken to determine the extent to which uPAR-mediated signaling is compartmentalized to lipid rafts. Human neutrophil uPAR was cross-linked or stimulated with uPA after pretreatment with the lipid raft-disrupting agents, methyl-beta-cyclodextrin or filipin III. Both agents suppressed increases in intracellular Ca(2+) concentrations ([Ca(2+)](i)) triggered by cross-linking, but did not affect [Ca(2+) ](i) in response to uPA. Neutrophil membranes were separated into lipid raft and non-raft fractions, revealing the presence of uPAR and L-selectin, but the virtual absence of CR3 alpha chain in lipid rafts, either constitutively or in response to uPAR aggregation. Fluorescence resonance energy transfer experiments confirmed close proximity of a lipid raft marker to both uPAR and L-selectin, but not CR3. We conclude that uPAR can engage distinct signaling pathways involving different partner proteins that are functionally and physically segregated from one another in both lipid raft and non-raft domains of the plasma membrane.

Animals↗
PubMed1975

Intestinal metabolism of plasma free fatty acids. Intracellular compartmentation and mechanisms of control.

Fatty acid metabolism in intestinal mucosa has been examined primarily in regard to lipid absorption. Since earlier studies suggested intestinal utilization of plasma free fatty acids (FFA), we investigated mucosal metabolism of plasma FFA in rats. Mucosal radioactivity (1 per cent of administered) was maximal 2 min after i.v. [14C]palmitate. Of mucosal 14C, 42 percent was in water-soluble metabolites, including CO2 and ketoacids, 28 percent in phospholipids, and only 16 per cent in triglycerides. The specific activity of mucosal triglyceride fatty acids (TGFA) was 11 times that of serum TGFA, confirming in situ synthesis. Double isotope experiments showed marked differences in the metabolism of fatty acids entering mucosa simultaneously from lumen and plasma. Whereas luminal fatty acids were chiefly esterified to triglyceride, plasma FFA were preferentially oxidized and incorporated into phospholipids. Crypts did not differ from villi, indicating that intestinal metabolism of plasma FFA is related to their site of entry into epithelial cells. Mucosal metabolism of i.v. [14C]palmitate was minimally affected by glucose administration. However, intraduodenal isocaloric ethanol inhibited mucosal oxidation of FFA by 60 per cent, and increased incorporation into triglycerides nearly twofold. During lipid absorption, mucosal uptake of plasma FFA doubled and incorporation into intestinal lymph triglycerides was increased sixfold. These studies demonstrate an intracellular compartmentation of fatty acids in the intestinal epithelium. In contrast to absorbed luminal fatty acids, plasma FFA in the fasting state are both an energy source and a substrate for the synthesis of tissue phospholipid. The fasting contribution of plasma FFA to mucosal and lymph triglyceride is minimal, but it increases during ethanol administration and fat absorption.

Animals↗
PubMed1982

Heterogeneity and compartmental properties of insulin storage and secretion in rat islets.

To investigate compartmental properties of insulin storage and secretion, isolated rat islets were used for pulse-labeling experiments, after which proinsulin and insulin were purified rigorously. Processing of proinsulin to insulin neared completion by 3 h without additional loss of either radioactive peptide by cellular or extracellular proteolysis. The amount of labeled hormone rapidly diminished in islets; it was secreted at a higher fractional rate than immunoreactive insulin, resulting in secreted insulin's having a higher specific activity than the average cellular insulin. Newly synthesized insulin, therefore, was secreted preferentially. Changes in the specific activity of secreted and cellular insulin with time were consistent with changes predicted for islets containing 33% of their total insulin in a glucose-labile compartment. Predictions were based on steady-state analysis of a simple storage-limited representation of B cell function. Islets from either the dorsal or ventral part of the pancreas also contained 33% of their total insulin in a glucose-labile compartment. The same compartment was mobilized by 20 mM glucose, 50 mM potassium + 2 mM glucose, or 20 MM glucose + 1 mM 3-isobutylmethylxanthine as indicated by the specific activity ratio of secreted vs. cellular insulin, even though average secretion rates with these stimuli differed by more than threefold. In the absence of calcium, the effectiveness of 20 mM glucose as a secretagogue declined markedly, and the older stored insulin was preferentially mobilized because secreted insulin had a lower rather than a higher specific activity than cellular insulin. Results provide insight into the mechanisms of nonrandom mobilization and secretion of insulin form the B cell.

Animals↗
PubMed1992

Human intraovarian interleukin-1 (IL-1) system: highly compartmentalized and hormonally dependent regulation of the genes encoding IL-1, its receptor, and its receptor antagonist.

To delineate the scope of the human intraovarian IL-1 system we used a solution hybridization/RNase protection assay to test for expression of the genes encoding IL-1, its type I receptor (IL-1R), and its receptor antagonist (IL-1RA). IL-1 transcripts were not detected in whole ovarian material from days 4 or 12 of an unstimulated menstrual cycle but transcripts (IL-1 beta much greater than IL-11 alpha) were detected in preovulatory follicular aspirates from gonadotropin-stimulated cycles. Concurrently obtained peripheral monocytes did not contain IL-1 beta transcripts but macrophage-depleted follicular aspirates did, thus implicating the granulosa cells as the site of IL-1 expression. IL-1R transcripts were detected in RNA from whole ovaries and follicular aspirates but not in RNA from peripheral monocytes. IL-1RA transcripts were detected in whole ovarian material as well as in macrophage-free follicular aspirates. Cultured human granulosa and theca cells did not contain mRNA for IL-1 beta or IL-1RA but did contain mRNA for IL-1R. Treatment of cell cultures with forskolin (25 microM) induced IL-1 beta transcripts in granulosa but not theca cells. Forskolin also increased the basal levels of IL-1R transcripts in both granulosa and theca cells but did not induce IL-RA transcripts in either cell type. Taken together, these findings reveal the existence of a complete, highly compartmentalized, hormonally dependent intraovarian IL-1 system replete with ligands, receptor, and receptor antagonist.

Adult↗
PubMed1997

Compartmentalization of angiotensin II generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces.

Angiotensin-converting enzyme inhibitors have beneficial effects that are presumably mediated by decreased angiotensin II (ANG II) production. In this study, we measure for the first time ANG I and ANG II levels in the interstitial fluid (ISF) space of the heart. ISF and aortic plasma ANG I and II levels were obtained at baseline, during intravenous infusion of ANG I (5 microM, 0.1 ml/min, 60 min), and during ANG I + the angiotensin-converting enzyme inhibitor captopril (cap) (2.5 mM, 0.1 ml/min, 60 min) in six anesthetized open-chested dogs. ISF samples were obtained using microdialysis probes inserted into the left ventricular myocardium (3-4 probes/dog). ANG I increased mean arterial pressure from 102+/-3 (SEM) to 124+/-3 mmHg (P < 0.01); addition of cap decreased MAP to 95+/-3 mmHg (P < 0.01). ANG I infusion increased aortic plasma ANG I and ANG II (pg/ml) (ANG I = 101+/-129 to 370+/-158 pg/ml, P < 0.01; and ANG II = 22+/-40 to 466+/-49, P < 0.01); addition of cap further increased ANG I (1,790+/-158, P < 0.01) and decreased ANG II (33+/-49, P < 0.01). ISF ANG I and ANG II levels (pg/ml) were > 100-fold higher than plasma levels, and did not change from baseline (8,122+/-528 and 6,333+/-677), during ANG I (8,269+/-502 and 6, 139+/-695) or ANG I + cap (8,753+/-502 and 5,884+/-695). The finding of very high ANG I and ANG II levels in the ISF vs. intravascular space that are not affected by IV ANG I or cap suggests that ANG II production and/or degradation in the heart is compartmentalized and mediated by different enzymatic mechanisms in the interstitial and intravascular spaces.

Angiotensin I↗
PubMed1997

Compartmental transfer of mercury released from amalgam.

The number of amalgam-covered surfaces and the occlusal area of the fillings, the concentrations of total mercury in plasma, erythrocytes and urine, the urinary excretion rate, and the absorbed daily doses estimated by two separate methods from intra-oral Hg emission were determined in 29 volunteers with a low amalgam load. The transfer of Hg from the fillings via the oral cavity and blood to urinary excretion was evaluated by multiple correlations between these variables. In addition, the combination of variables most representative of the entire compartmental transfer of amalgam Hg was determined. Urinary excretion (1), Hg concentration in plasma (2) and absorbed dose (3) were most closely correlated to each other, followed by correlations with the variables of the fillings (4). Correlation coefficients were 0.75 for variables 1 vs 2 and 2 vs 3, and 0.49 for variables 3 vs 4. It was concluded that variables 1-3 best reflected the transfer of mercury from amalgam fillings throughout the organism and that they were relatively insensitive to dietary mercury. The determination of total mercury in plasma and of its urinary excretion rate appears, under practical aspects, most suitable for the investigation of Hg uptake from amalgam.

Adult↗
PubMed1993

An anatomical study of the tarsal tunnel using low pressure compartmental infusion.

The anatomy of the tarsal tunnel is demonstrated using a low-pressure compartmental infusion technique. This is done by infusing colored radiopaque contrast material into three fresh cadaveric specimens. Thin section photography and computed tomography are then used to identify the boundaries and contents of the tarsal tunnel as it traverses the ankle, hindfoot, and midfoot. The tarsal tunnel is shown to communicate proximally with the deep posterior compartment of the leg and distally with the intermediate compartment of the forefoot. The relationships of the structures contained within the tarsal tunnel are shown in detail.

Ankle↗
PubMed2006

Regulatory T-cell compartmentalization and trafficking.

CD4(+)CD25(+)FOXP3(+) regulatory T cells (CD4(+) Treg cells) are thought to differentiate in the thymus and immigrate from the thymus to the periphery. Treg cells can regulate both acquired and innate immunity through multiple modes of suppression. The cross-talk between Treg cells and targeted cells, such as antigen-presenting cells (APCs) and T cells, is crucial for ensuring suppression by Treg cells in the appropriate microenvironment. Emerging evidence suggests that Treg compartmentalization and trafficking may be tissue or/and organ specific and that distinct chemokine receptor and integrin expression may contribute to selective retention and trafficking of Treg cells at sites where regulation is required. In this review, the cellular and molecular signals that control specialized migration and retention of Treg cells are discussed.

Chemokines↗
PubMed2025

Multi-omics analysis reveals distinct spatial compartmentalization of lung repair niches in pediatric ARDS.

BACKGROUND: Pediatric acute respiratory distress syndrome (PARDS), often triggered by viral infections, is a life-threatening condition. Despite its severity, children demonstrate significantly better survival rates and superior lung repair compared to adults. However, the mechanisms underlying this age-specific advantage remain incompletely understood. PATIENTS AND METHODS: We conducted a pilot multi-omics study of influenza-associated PARDS integrating single-cell RNA sequencing (scRNA-seq) of pediatric lung tissue and bronchoalveolar lavage fluid (BALF), spatial transcriptomics, and plasma proteomics. Analyses were harmonized with the Human Lung Cell Atlas (HLCA) reference, reanalysis of public pediatric PARDS airway scRNA-seq, and contextual comparisons to adult lethal COVID-19 lung. RESULTS: Tissue scRNA-seq and spatial data indicated outcome-linked divergence in PARDS. Survivor showed spatially restricted repair with preserved alveolar type II (AT2) cells, AT2-to-alveolar type I (AT1) differentiation signatures, and higher KRT17, whereas fatal case and adults exhibited diffuse immune activation with pro-fibrotic and pro-apoptotic signaling. In BALF, KRT17-positive airway stress&#x2013;repair epithelial cells (hillock-like) increased from the acute to recovery phase, and plasma proteomics showed higher circulating KRT17 in survivors. HLCA-based label transfer strengthened cell-type definitions and enabled pediatric&#x2013;adult comparisons suggesting biological and developmental differences; the adult lethal COVID-19 atlas provided a benchmark with attenuated epithelial repair and prominent collagen CTHRC1-pathologic fibroblasts. Fibroblast programs were regionally compartmentalized, with injury-enriched CTHRC1+ states versus alveolar fibroblasts in preserved areas, and showed stronger injury&#x2013;homeostasis anti-correlation in fatalities. Myeloid remodeling included BALF transitions from FCN1-high inflammatory states toward FABP4-positive resident-like states, consistent with public pediatric datasets showing reduced inflammatory and interferon-stimulated gene (ISG) modules and severity-linked increases in aged neutrophils. CONCLUSIONS: This pilot multi-omics case series outlines putative pediatric lung repair niches in influenza-associated PARDS. KRT17-positive transitional epithelium, preserved AT2 differentiation, and restoration of resident-like macrophages may align with recovery, whereas diffuse immune activation and CTHRC1-enriched fibroblast programs may accompany worse outcomes. HLCA-guided annotations and adult benchmarks indicate possible age-related differences, warranting validation in larger multi-center cohorts.

Humans↗
PubMed2006

Compartmental analyses of plasma 13C- and 2H-labeled n-6 fatty acids arising from oral administrations of 13C-U-18:2n-6 and 2H5-20:3n-6 in newborn infants.

Efficacy of (13)C-U-18:2n-6 and (2)H(5)-20:3n-6 toward synthesis of labeled-20:4n-6 was studied in newborn infants utilizing compartmental models of plasma labeled n-6 fatty acids (FA). Ten infants received oral doses of (13)C-U-18:2n-6 and (2)H(5)-20:3n-6 ethyl esters (100 and 2 mg/kg, respectively). Rate constant coefficients and half-lives (t((1/2))) of n-6 FA were determined from the time-course concentrations of labeled-FA. Plasma n-6 FA values approximated steady state concentrations. Synthetic and utilization rates were calculated. Eight percent (range, 2-21%) of plasma (13)C-U-18:2n-6 was used for synthesis of (13)C-18:3n-6, -20:2n-6, and -20:3n-6. Seventy percent of (13)C-20:3n-6 (mean, CV: 0.26) was available for synthesis of (13)C-20:4n-6. The percentage of (2)H(5)-20:3n-6 converted to (2)H(5)-20:4n-6 was lower (mean: 26%, p < 0.02) than the (13)C-labeled analogue. Turnover of 18:2n-6 in subjects and of 20:4n-6 in plasma was 4.2 g/kg/d (CV: 0.58) and 4.3 mg/kg/d (CV: 0.81), respectively. Intake of 18:2n-6 and 20:4n-6 were estimated to be 3.0 g/kg/d (+/-1.7) and 2.8 mg/kg/d (+/- 2.2), respectively. Infants required additional 18:2n-6 and 20:4n-6 (mean: 1.2 g and 1.5 mg/kg/d) above predicted intake amounts to maintain plasma concentrations of 18:2n-6 and 20:4n-6, in order to spare FA from fat stores.

8,11,14-Eicosatrienoic Acid↗
PubMed2004

Estrogen directly induces expression of retinoic acid biosynthetic enzymes, compartmentalized between the epithelium and underlying stromal cells in rat uterus.

Estrogen (E2) has been shown to induce the biosynthesis of retinoic acid (RA) in rat uterus. Here we examined whether E2 could directly induce the enzymes involved in this process by using the ovariectomized rat. A retinol dehydrogenase that we have previously described, eRolDH, and the retinal dehydrogenase, RalDH II, were found to have markedly increased uterine mRNA levels within 4 h of E2 administration, independent of the prior administration of puromycin. eRolDH and RalDH II and their mRNAs were also increased in uteri of rats during estrus. This indicated that RA biosynthesis in rat uterus is directly controlled by E2 and provides a direct link between the action of a steroid hormone and retinoid action. We also examined the cell-specific localization of RalDH II by immunohistochemistry. The enzyme was observed in the stromal compartment, particularly in cells close to the uterine lumenal epithelium. eRolDH was observed only in the lining epithelial cells. Taken together with the previous observations of cellular retinol-binding protein and cellular retinoic acid-binding protein, type two also being expressed in the lumenal epithelium, we propose that RA production is compartmentalized, with retinol oxidation occurring in the lumenal epithelium and subsequent oxidation of retinal to RA occurring in the underlying stromal cells.

Alcohol Oxidoreductases↗
PubMed1984

Evidence for alteration in the processing of dopamine in the anterior pituitary gland of aged rats: receptors and intracellular compartmentalization of dopamine.

Receptors for dopamine and the subcellular localization of dopamine in the anterior pituitary gland were studied in young cycling female rats and in aged, constant estrous female rats. Dopamine receptors were quantified in membrane preparations of anterior pituitary tissue using [3H] spiperone as the ligand. On the basis of saturation isotherms, it was calculated that the equilibrium dissociation constant (Kd) and binding capacity for [3H]spiperone binding to pituitary membranes from young rats were 34.2 pM and 82 fmol/mg protein, respectively. The relative binding capacity of membranes from aged rats was 35% greater than that of membranes from young rats. There was no difference in the Kd values in aged and young rats. When the relative binding of [3H]spiperone by anterior pituitary membranes from individual animals was quantified by incubation with a saturating concentration of the ligand, it was found that [3H]spiperone binding in aged rats was significantly greater than that in young rats. When the subcellular localization of dopamine in anterior pituitary tissue was examined by means of density gradient centrifugation, it was found that the subcellular distribution of dopamine in tissue of aged rats was quantitatively different from that in young rats. In young rats, a small amount of dopamine was associated with light particles, whereas a large amount of dopamine was associated with heavy particles, which cosedimented with PRL-containing granules. In aged rats, the amount of dopamine associated with light particles was 5 times that found in young rats, whereas the amount of dopamine associated with heavy particles was the same as that in young rats. We speculate that altered intracellular compartmentalization of dopamine, leading to a marked accumulation of dopamine in the light particles, is related to increased secretion of PRL in aged rats.

Aging↗
PubMed1991

Evidence for compartmentalization of adenosine 3',5'-monophosphate (cAMP)-dependent protein kinases in rat Leydig cells using site-selective cAMP analogs.

It is generally believed that LH-stimulated steroidogenesis in Leydig cells is via activation of the cAMP second messenger system. The present study used cAMP analogs selective in their binding to the two types of cAMP-dependent protein kinase (PK-A) and/or selective in their binding to the two cAMP-binding sites on the regulatory subunits of PK-A. As the two cAMP-binding sites show positive cooperativity, synergistic increases in androgen production by rat Leydig cells occurred when they were incubated in vitro with analog pairs that selectively activated PK-A type I or II. This confirmed that both types of PK-A are present in Leydig cells and demonstrated that both PK-A types are capable of activating steroidogenesis. Synergistic increases in androgen production were also observed when either a type I selective analog (8-aminohexylamino-cAMP) or a type II selective analog (8-thiomethyl-cAMP) was paired with added cAMP. However, when these analogs were paired with LH or the adenylate cyclase activator forskolin, a synergistic increase in steroidogenesis occurred only with the type I selective analog. These results suggest that PK-A type I is compartmentalized in Leydig cells so that it has preferential access to endogenously produced cAMP.

Animals↗
PubMed2005

The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity.

ERK MAP kinase signaling plays a pivotal role in diverse cellular functions, including cell proliferation, differentiation, migration and survival. One of the central questions concerning this signaling is how activation of the same protein kinase, ERK, elicits distinct cellular outcomes. Recent progress has demonstrated that differences in the duration, magnitude and subcellular compartmentalization of ERK activity generate variations in signaling output that regulate cell fate decisions. Furthermore, several molecules have been identified as spatial, temporal or strength-controlling regulators of ERK activity. Signaling by various extracellular stimuli thus could be modulated by these regulators to give qualitative and quantitative differences in ERK activity, which are then interpreted by the cells as determinants for appropriate responses.

Animals↗