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PubMed2002

Transport-mediated synapses in the retina.

Most synapses rely on regulated exocytosis for determining the concentration of transmitter in the synaptic cleft. However, this mechanism may not be universal. Several synapses in the retina appear to use a synaptic machinery in which transmitter transporters play an essential role. Two types of transport-mediated synapses have been proposed. These synapses have been best observed in horizontal cells and cones of nonmammalian retinas. Horizontal cells use a transporter to mediate a bidirectional shuttle, whose balance point is set by ion concentrations and voltage. Nonmammalian cones combine exocytosis and the activity of a transporter. Because exocytosis is voltage independent over most of a cone's physiological voltage range, a voltage-dependent transporter determines the concentration of transmitter in the synaptic cleft. These two synapses may be models for transport-mediated synapses that operate in other parts of the brain.

Animals↗

PubMed2002

Interaction of human organic anion transporters with various cephalosporin antibiotics.

Cephalosporin antibiotics are thought to be excreted into the urine via organic anion transporters (OATs). The purpose of this study was to elucidate the interaction of human-OATs with various cephalosporin antibiotics, using proximal tubule cells stably expressing human-OAT1, human-OAT3 and human-OAT4. Human-OAT1 and human-OAT3 are localized to the basolateral side of the proximal tubule, whereas human-OAT4 is localized to the apical side. The cephalosporin antibiotics tested were cephalothin, cefoperazone, cefazolin, ceftriaxone, cephaloridine, cefotaxime, cefadroxil and cefamandole. All of these cephalosporin antibiotics significantly inhibited organic anion uptake mediated by human-OAT1, human-OAT3 and human-OAT4. Kinetic analysis revealed that these inhibitions were competitive. The inhibition constant (K(i)) values of cefoperazone, cefazolin, ceftriaxone and cephaloridine for human-OAT1 were much lower than those for human-OAT3 and human-OAT4, whereas the K(i) values of cephalothin and cefotaxime for human-OAT3 were much lower than those for human-OAT1 and human-OAT4. Human-OAT4 mediated the bidirectional transport of estrone sulfate, an optimal substrate for human-OAT4. These results suggest that human-OAT1, human-OAT3 and human-OAT4 interact with various cephalosporin antibiotics, and that human-OAT1 and human-OAT3 play a distinct role in the basolateral uptake of cephalosporin antibiotics. Since the K(i) value of cephaloridine for human-OAT4-mediated organic uptake was much higher than that for human-OAT1, the results indicate the possibility that human-OAT4 limits the efflux of cephaloridine, leading to the accumulation of cephaloridine and the induction of nephrotoxicity.

Animals↗

PubMed1999

Spatial response properties of contralateral inhibited lobula plate tangential cells in the fly visual system.

This study describes the spatial response properties of a particular group of motion-sensitive and directionally selective neurons located in the lobula plate of the fly visual system. Their preferred motion direction is front-to-back (depolarization), and their null direction is back-to-front (hyperpolarization). They receive inhibitory input from the contralateral eye during pattern motion from back to front (regressive). In this study, we call these neurons regressive contralateral inhibited lobula plate tangential cells (rCI-LPTCs). Three physiologic groups of rCI-neurons (rCI-I, rCI-IIa, and rCI-IIb) can be distinguished on the basis of their ipsilateral pattern size dependence and their inhibitory contralateral input. rCI-I neurons depolarize during the motion of small ipsilateral patterns from front to back, but they become hyperpolarized by large ipsilateral patterns moving in the same direction. rCI-IIa and rCI-IIb neurons receive bidirectional inhibitory input from the contralateral eye. rCI-IIa neurons respond best to small ipsilateral pattern sizes, but unlike rCI-I neurons, their net response to large patterns is positive. rCI-IIb neurons respond best to large ipsilateral patterns. The anatomical and physiologic variability of the rCI-neurons suggests that more than three types of rCI-neurons exist. The suggested physiologic groups might be preliminary. We recorded one neuron that could mediate the bidirectional inhibitory input that rCI-IIa and rCI-IIb neurons receive from the contralateral eye. In the case of the rCI-IIa neurons at least one further contralateral inhibitory element has to be assumed. The tuning of rCI-IIa neurons to small ipsilateral pattern sizes is likely to be based on an on-center/off-surround organization of their synaptic input.

Animals↗

PubMed1999

Lipid transfer inhibitor protein defines the participation of lipoproteins in lipid transfer reactions: CETP has no preference for cholesteryl esters in HDL versus LDL.

Cholesteryl ester transfer protein (CETP) catalyzes the net transfer of cholesteryl ester (CE) between lipoproteins in exchange for triglyceride (heteroexchange). It is generally held that CETP primarily associates with HDL and preferentially transfers lipids from this lipoprotein fraction. This is illustrated in normal plasma where HDL is the primary donor of the CE transferred to VLDL by CETP. However, in plasma deficient in lipid transfer inhibitor protein (LTIP) activity, HDL and LDL are equivalent donors of CE to VLDL (Arterioscler Thromb Vasc Biol. 1997;17:1716-1724). Thus, we have hypothesized that the preferential transfer of CE from HDL in normal plasma is a consequence of LTIP activity and not caused by a preferential CETP-HDL interaction. We have tested this hypothesis in lipid mass transfer assays with partially purified CETP and LTIP, and isolated lipoproteins. With a physiological mixture of lipoproteins, the preference ratio (PR, ratio of CE mass transferred from a lipoprotein to VLDL versus its CE content) for HDL and LDL in the presence of CETP alone was approximately 1 (ie, no preference). Fourfold variations in the LDL/HDL ratio or in the levels of HDL in the assay did not result in significant preferential transfer from any lipoprotein. On addition of LTIP, the PR for HDL was increased up to 2-fold and that for LDL decreased in a concentration-dependent manner. Under all conditions where LDL and HDL levels were varied, LTIP consistently resulted in a PR >1 for CE transfer from HDL. Short-term experiments with radiolabeled lipoproteins and either partially purified or homogenous CETP confirmed these observations and further demonstrated that CETP has a strong predilection to mediate homoexchange (bidirectional transfer of the same lipid) rather than heteroexchange (CE for TG); LTIP had no effect on the selection of CE or TG by CETP or its mechanism of action. We conclude, in contrast to current opinion, that CETP has no preference for CE in HDL versus LDL, suggesting that the previously reported stable binding of CETP to HDL does not result in selective transfer from this lipoprotein. These data suggest that LTIP is responsible for the preferential transfer of CE from HDL that occurs in plasma. CETP and LTIP cooperatively determine the extent of CETP-mediated remodeling of individual lipoprotein fractions.

Apolipoproteins↗

PubMed2026

Gender-specific pathways linking body dissatisfaction, self-disgust, and social anxiety in Chinese adolescents: A three-wave longitudinal study.

Adolescence is a critical period for physical and psychological development. Body dissatisfaction is a significant concern during this stage, contributing to psychological issues such as social anxiety. However, the longitudinal relationships among body dissatisfaction, self-disgust, and social anxiety, as well as the potential role of gender differences in these dynamics, remain unclear. A total of 1109 junior high school students in China completed the baseline survey, with data collected at three time points (Mage = 12.67 years, SD = 0.68; 51.9% girls). Data were collected using the Body Areas Satisfaction Scale (BASS), the Self-Disgust Scale (SDS), and the Social Anxiety Scale for Children (SASC). Structural equation modeling (SEM) was employed to examine the longitudinal mediating effects among body dissatisfaction, self-disgust, and social anxiety, as well as to explore gender differences in these relationships. After controlling for autoregressive effects of self-disgust and social anxiety across waves, body dissatisfaction at T1 was found to indirectly predict social anxiety at T3 through self-disgust at T2, while indirectly predicting self-disgust at T3 through social anxiety at T2. Multi-group analyses revealed significant gender differences: for females, only the mediating pathway with self-disgust as the mediator was significant; for males, only the pathway with social anxiety as the mediator was significant. These findings contribute to a more nuanced understanding of the emotional mechanisms linking body dissatisfaction to social anxiety and highlight the importance of considering gender-specific pathways in prevention and intervention efforts.

Adolescent↗

PubMed2004

A CaMKII/calcineurin switch controls the direction of Ca(2+)-dependent growth cone guidance.

Axon pathfinding depends on attractive and repulsive turning of growth cones to extracellular cues. Localized cytosolic Ca2+ signals are known to mediate the bidirectional responses, but downstream mechanisms remain elusive. Here, we report that calcium-calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) phosphatase provide a switch-like mechanism to control the direction of Ca(2+)-dependent growth cone turning. A relatively large local Ca2+ elevation preferentially activates CaMKII to induce attraction, while a modest local Ca2+ signal predominantly acts through CaN and phosphatase-1 (PP1) to produce repulsion. The resting level of intracellular Ca2+ concentrations also affects CaMKII/CaN operation: a normal baseline allows distinct turning responses to different local Ca2+ signals, while a low baseline favors CaN-PP1 activation for repulsion. Moreover, the cAMP pathway negatively regulates CaN-PP1 signaling to inhibit repulsion. Finally, CaMKII/CaN-PP1 also mediates netrin-1 guidance. Together, these findings establish a complex Ca2+ mechanism that targets the balance of CaMKII/CaN-PP1 activation to control distinct growth cone responses.

Animals↗

PubMed2006

The negative c-Myc target onzin affects proliferation and apoptosis via its obligate interaction with phospholipid scramblase 1.

Onzin, the product of a negatively c-Myc-regulated target gene, is highly expressed in myeloid cells. As a result of its interaction with and activation of Akt1 and Mdm2, onzin down-regulates p53. The apoptotic sensitivity of several cell lines is thus directly related to onzin levels. We have conducted a search for additional onzin-interacting proteins and identified phospholipid scramblase 1 (PLSCR1), an endofacial membrane protein, which is proposed to mediate the bidirectional movement of plasma membrane phospholipids during proliferation and apoptosis. PLSCR1 interacts with the same cysteine-rich domain of onzin as do Akt1 and Mdm2, whereas the onzin-interacting domain of PLSCR1 centers around, but does not require, a previously identified palmitoylation signal. Depletion of endogenous PLSCR1 in myeloid cells leads to a phenotype that mimics that of onzin overexpression, providing evidence that PLSCR1 is a physiologic regulator of onzin. In contrast, PLSCR1 overexpression in fibroblasts, which normally do not express onzin, affects neither growth nor apoptosis unless onzin is coexpressed, in which case PLSCR1 completely abrogates onzin's positive effects on proliferation and survival. These findings demonstrate a functional interdependence between onzin and PLSCR1. They further suggest a contiguous link between the earliest events mediated by c-Myc and the latest ones, which culminate at the cell surface and lead to phospholipid reshuffling and cell death.

Animals↗

PubMed1994

Promoter and operator determinants for fur-mediated iron regulation in the bidirectional fepA-fes control region of the Escherichia coli enterobactin gene system.

The fepA-entD and fes-entF operons in the enterobactin synthesis and transport system are divergently transcribed from overlapping promoters, and both are inhibited by the Fur repressor protein under iron-replete conditions. A plasmid harboring divergent fepA'-phoA and fes-entF'-'lacZ fusions, both under the control of this bidirectional regulatory region, was constructed for the purpose of monitoring changes in expression of the two operons simultaneously. Deletion analysis, site-directed mutagenesis, and primer extension were employed to define both a single promoter governing the expression of fes-entF and two tandemly arranged promoters giving rise to the opposing fepA-entD transcript. A single Fur-binding site that coordinately regulates the expression of all transcripts emanating from this control region was identified by in vitro protection from DNase I nicking. The substitution of one base pair in the Fur recognition sequence relieved Fur repression but did not change the in vitro affinity of Fur for its binding site. Additional mutations in a limited region outside of the promoter determinants for either transcript inhibited expression of both fes and fepA. These observations suggest a mechanism of Fur-mediated regulation in this compact control region that may involve other regulatory components.

Bacterial Outer Membrane Proteins↗

PubMed2004

Accurate bidirectional saccade control by a single hemicortex.

Anatomical, electrophysiological and lesion studies indicate that each cortical hemisphere normally generates saccades directed to the contralateral side. In contrast, in patients who had an entire cortical hemisphere removed surgically (hemidecortication), the remaining hemicortex can generate both contraversive and ipsiversive saccades. However, current evidence indicates that ipsiversive saccades are grossly inaccurate. The obvious reason for this is that hemidecorticate patients are blind in the hemifield ipsilateral to the remaining hemicortex, and therefore normal visual signals are not available to drive ipsiversive saccades. However, absent vision also implies that visual error signals are not available to calibrate ipsiversive movements. Furthermore, the innate anatomical substrate needed to support accurate ipsiversive saccade control, in addition to the normal contraversive control, appears sparse. We show here that, in spite of these obstacles, hemidecorticate patients could generate accurate ipsiversive saccades in a task that dissociated hemianopia from saccade direction. In this task, while the patients fixated a central fixation target (FT), saccade targets (STs) were briefly presented to the intact visual hemifield contralateral to the intact hemicortex. The FT was then moved towards and beyond the former location of the ST which evoked tracking eye movements that moved the eyes towards and then beyond the ST, thereby moving the goal, ST, into the blind visual hemifield ipsilateral to the intact hemicortex. When the FT was extinguished, the patients generated, in the dark, ipsiversive saccades that moved their eyes to the remembered location of the ST with the same accuracy as normal control subjects. This indicates that a single hemicortex can mediate accurate bidirectional saccade control via fully functional bilateral connections from cortex to brainstem oculomotor structures. The mechanisms whereby visual signals can calibrate ipsiversive saccades remain elusive.

Adolescent↗

PubMed2006

Role of neuronal NR2B subunit-containing NMDA receptor-mediated Ca2+ influx and astrocytic activation in cultured mouse cortical neurons and astrocytes.

The excitatory neurotransmitter glutamate has been shown to mediate such bidirectional communication between neurons and astrocytes. In the present study, we determined the role of N-methyl-D-aspartate (NMDA) receptors on glutamate-evoked Ca(2+) influx into neurons and astrocytes. Either a nonselective NMDA receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) or selective NR2B subunit-containing NMDA receptor antagonists ifenprodil and (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (Ro25-6981) significantly inhibited the glutamate-evoked Ca(2+) influx into neurons, but not into astrocytes. Furthermore, we investigated whether NR2B subunit-containing NMDA receptor antagonists could suppress the astrocytic activation, as detected by glial fibrillary acidic protein (GFAP; as a specific marker of astrocyte)-like immunoreactivities in mouse cortical astrocytes. Here, we demonstrated that the increases in the level of GFAP-like immunoreactivities induced by glutamate were markedly suppressed by cotreatment with ifenprodil in cortical neuron/glia cocultures, but not in purified astrocytes. These results suggest that NR2B subunit-containing NMDA receptor plays a critical role in not only glutamate-evoked Ca(2+) influx into neurons, but also glutamate-induced astrocytic activation. Thus, glutamate-mediated pathway via NR2B subunit-containing NMDA receptor may, at least in part, contribute to neuron-to-astrocyte signaling.

Aniline Compounds↗

PubMed2001

The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals.

Bidirectional signals mediated by membrane-anchored ephrins and Eph receptor tyrosine kinases have important functions in cell-cell recognition events, including those that occur during axon pathfinding and hindbrain segmentation. The reverse signal that is transduced into B-ephrin-expressing cells is thought to involve tyrosine phosphorylation of the signal's short, conserved carboxy-terminal cytoplasmic domain. The Src-homology-2 (SH2) domain proteins that associate with activated tyrosine-phosphorylated B-subclass ephrins have not been identified, nor has a defined cellular response to reverse signals been described. Here we show that the SH2/SH3 domain adaptor protein Grb4 binds to the cytoplasmic domain of B ephrins in a phosphotyrosine-dependent manner. In response to B-ephrin reverse signalling, cells increase FAK catalytic activity, redistribute paxillin, lose focal adhesions, round up, and disassemble F-actin-containing stress fibres. These cellular responses can be blocked in a dominant-negative fashion by expression of the isolated Grb4 SH2 domain. The Grb4 SH3 domains bind a unique set of other proteins that are implicated in cytoskeletal regulation, including the Cbl-associated protein (CAP/ponsin), the Abl-interacting protein-1 (Abi-1), dynamin, PAK1, hnRNPK and axin. These data provide a biochemical pathway whereby cytoskeletal regulators are recruited to Eph-ephrin bidirectional signalling complexes.

Adaptor Proteins, Signal Transducing↗

PubMed1989

Human tonsillar dendritic cell-induced T cell responses: analysis of molecular mechanisms using monoclonal antibodies.

Dendritic cells, isolated from human tonsillar tissue, were found to be potent stimulators of the sodium periodate T cell oxidative mitogenesis reaction. Monoclonal antibodies against CD2, CD4, CD11a, CD18, LFA-3, ICAM-1, class I and class II major histocompatibility complex (MHC) inhibited T cell proliferation in this response, whereas antibodies against CD8, CD11b, CD11c and CD16 had no effect. Further, antibodies against CD2, CD11a, CD18, LFA-3 and ICAM-1 inhibited the early dendritic cell-T cell clustering event which occurs in this cell interaction. In contrast, antibodies against CD4, class I and class II MHC did not inhibit clustering. Studies examining the expression of the respective molecules upon isolated dendritic cells and T cells suggest that anti-LFA-3 and anti-class II MHC antibodies inhibit at the level of the dendritic cell, whereas anti-CD2 and anti-CD4 antibodies inhibit at the level of the T cell. However, antibodies against CD11a, CD18, ICAM-1 and class I MHC may inhibit at either or both cell levels. These findings have enabled us to propose a molecular mechanism for dendritic cell-T cell interaction in oxidative mitogenesis. Dendritic cell-T cell clustering is mediated by bidirectional binding of LFA-1 (CD11a and CD18) and ICAM-1 (involving both molecules on both cell types) and unidirectional binding of CD2 and LFA-3 (involving T cell CD2 and dendritic cell LFA-3). This initial event permits a second interaction of dendritic cell and T cell molecules, involving T cell CD4, class I MHC (possibly at both cellular levels) and dendritic cell class II MHC, which deliver the signal for proliferation.

Antibodies, Monoclonal↗

PubMed2002

Modifications in astrocyte morphology and calcium signaling induced by a brain capillary endothelial cell line.

Astrocytes extend specialized endfoot processes to perisynaptic and perivascular regions, and thus are positioned to mediate the bidirectional flow of metabolic, ionic, and other transmissive substances between neurons and the blood stream. While mutual structural and functional interactions between neurons and astrocytes have been documented, less is known about the interactions between astrocytes and cerebrovascular cells. For example, although the ability of astrocytes to induce structural and functional changes in endothelial cells is established, the reciprocity of brain endothelial cells to induce changes in astrocytes is undetermined. This issue is addressed in the present study. Changes in primary cultures of neonatal mouse cortical astrocytes were investigated following their coculture with mouse brain capillary endothelial (bEnd3) cells. The presence of bEnd3 cells altered the morphology of astrocytes by transforming them from confluent monolayers into networks of elongated multicellular columns. These columns did not occur when either bEnd3 cells or astrocytes were cocultured with other cell types, suggesting that astrocytes undergo specific morphological consequences when placed in close proximity to brain endothelial cells. In addition to these structural changes, the pharmacological profile of astrocytes was modified by coculture with bEnd3 cells. Astrocytes in the cocultures showed an increased Ca2+ responsiveness to bradykinin and glutamate, but no change in responsiveness to ATP, as compared to controls. Coculturing the astrocytes with a neuronal cell line resulted in increased responsiveness of the glial responses to glutamate but not to bradykinin. These studies indicate that brain endothelial cells induce changes in astrocyte morphology and pharmacology.

Animals↗

PubMed2006

EphB2 and ephrin-B2 regulate the ionic homeostasis of vestibular endolymph.

The ability to transport cations and anions across epithelia is critical for the regulation of pH, ionic homeostasis, and volume of extracellular fluids. Although the transporters and channels that facilitate ion and water movement across cell membranes are well known, the molecular mechanisms and signal transduction events that regulate these activities remain poorly understood. The Eph family of receptor tyrosine kinases and their membrane-anchored ephrin ligands are well known to transduce bidirectional signals that control axon guidance and other cell migration/adhesion events during development. However, these molecules are also expressed in non-motile epithelial cells, including EphB2 in K(+)-secreting vestibular dark cells and ephrin-B2 in the adjacent transitional cells of the inner ear. Consistent with these expression patterns, mice with cytoplasmic domain mutations that interfere with EphB2 forward signaling or ephrin-B2 reverse signaling exhibit a hyperactive circling (waltzing) locomotion associated with a decreased amount of endolymph fluid that normally fills the vestibular labyrinth. Endolymph is unusual as an extracellular fluid in that it is normally high in K(+) and low in Na(+). Direct measurement of this fluid in live animals revealed significant decreases in K(+) concentration and endolymphatic potential in both EphB2 and ephrin-B2 mutant mice. Our findings provide evidence that bidirectional signaling mediated by B-subclass Ephs and ephrins controls the production and ionic homeostasis of endolymph fluid and thereby provide the first evidence that these molecules can control the activities of mature epithelial cells.

Animals↗

PubMed2000

A novel, nuclear pore-associated, widely distributed molecule overexpressed in oncogenesis and development.

Nuclear pore complexes are large, elaborate macromolecular structures that mediate the bidirectional nucleocytoplasmic traffic. In vertebrates, nuclear pore complexes comprise 50 to 100 proteins termed nucleoporins (Nup). An 88-kd nucleoporin (Nup88) has been recently cloned and characterized, and found to be associated in a dynamic subcomplex with the oncogenic nucleoporin CAN/Nup 214. We have produced a polyclonal antiserum to Nup88, and found that it immunoreacts convincingly in conventional tissue sections of 214 samples of malignant tumors of many types. All carcinomas were stained irrespective of site or line of differentiation; the majority of cases reacted strongly and extensively. In situ carcinomas and highly dysplastic epithelia were similarly reactive. Samples of malignant mesotheliomas, gliomas, sarcomas, and lymphoreticular tumors were also stained. Substantial reactions were also found in certain fetal tissues. Focal reactions were noted in some reactive-proliferative processes. Most benign epithelial and mesenchymal tumors and hyperplasias, and normal adult tissues reacted weakly and sporadically or not at all. Immunoblot analysis of selected samples strongly corroborated those findings. If further substantiated, our findings indicate that Nup88 could be regarded as a selective yet broadly based proliferation marker of potential significance in the histological evaluation and diagnosis of malignant transformation. Its ready applicability on conventional paraffin sections and on cytological preparations may broaden its clinical and investigative significance.

Adult↗

PubMed1997

Integrin cytoplasmic domains as connectors to the cell's signal transduction apparatus.

Integrins mediate the bidirectional transfer of signals across the plasma membrane. Integrin cytoplasmic domains provide one pathway linking integrin engagement with the cell's signal transduction apparatus. Recent structure-function studies have defined regions of beta cytoplasmic domains required for integrin function and have identified distinct roles for individual alpha cytoplasmic domains in regulating cell behavior. Newly identified proteins that bind to integrin alpha and beta cytoplasmic domains have provided new insights and new questions into the mechanisms involved in integrin signaling.

Amino Acid Sequence↗

PubMed2002

Cytokines and cognition--the case for a head-to-toe inflammatory paradigm.

The brain is not only immunologically active of its own accord, but also has complex peripheral immune interactions. Given the central role of cytokines in neuroimmmunoendocrine processes, it is hypothesized that these molecules influence cognition via diverse mechanisms. Peripheral cytokines penetrate the blood-brain barrier directly via active transport mechanisms or indirectly via vagal nerve stimulation. Peripheral administration of certain cytokines as biological response modifiers produces adverse cognitive effects in animals and humans. There is abundant evidence that inflammatory mechanisms within the central nervous system (CNS) contribute to cognitive impairment via cytokine-mediated interactions between neurons and glial cells. Cytokines mediate cellular mechanisms subserving cognition (e.g., cholinergic and dopaminergic pathways) and can modulate neuronal and glial cell function to facilitate neuronal regeneration or neurodegeneration. As such, there is a growing appreciation of the role of cytokine-mediated inflammatory processes in neurodegenerative diseases such as Alzheimer's disease and vascular dementia. Consistent with their involvement as mediators of bidirectional communication between the CNS and the peripheral immune system, cytokines play a key role in the hypothalamic-pituitary-adrenal axis activation seen in stress and depression. In addition, complex cognitive systems such as those that underlie religious beliefs, can modulate the effects of stress on the immune system. Indirect means by which peripheral or central cytokine dysregulation could affect cognition include impaired sleep regulation, micronutrient deficiency induced by appetite suppression, and an array of endocrine interactions. Given the multiple levels at which cytokines are capable of influencing cognition it is plausible that peripheral cytokine dysregulation with advancing age interacts with cognitive aging.

Aging↗

PubMed1996

Isolation of an erythrocyte membrane protein that mediates Ca2+-dependent transbilayer movement of phospholipid.

Elevation of intracellular Ca2+ in erythrocytes, platelets, and other cells initiates rapid redistribution of plasma membrane phospholipids (PL) between inner and outer leaflets, collapsing the normal asymmetric distribution. Consequently, phosphatidylserine and other lipids normally sequestered to the inner leaflet become exposed at the cell surface. This Ca2+-induced mobilization of phosphatidylserine to the surface of activated, injured, or apoptotic cells confers a procoagulant property to the plasma membrane, which promotes fibrin clotting and provides a signal for cell removal by the reticuloendothelial system. To identify the constituent of the membrane that mediates this Ca2+-dependent "PL scramblase" activity, we undertook purification and reconstitution of membrane component(s) with this activity from detergent extracts of erythrocyte ghosts depleted of cytoskeleton. Active fractions were identified by their capacity to mediate the Ca2+-dependent redistribution of 7-nitrobenz-2-oxa-1,3-diazol-4-yl-labeled PL between leaflets of reconstituted proteoliposomes. This PL scramblase activity co-eluted through multiple chromatographic steps with a single polypeptide of approximately 37 kDa, which was purified to apparent homogeneity as resolved by silver staining. The activity associated with this protein band was inactivated by trypsin. The isolated protein reconstituted in proteoliposomes mediated nonselective, bidirectional transport of 7-nitrobenz-2-oxa-1, 3-diazol-4-yl-PL between membrane leaflets, with half-maximal activation between 20 and 60 microM Ca2+ (saturation >100 microM), mimicking the Ca2+-dependent transbilayer lipid movement intrinsic to the erythrocyte membrane.

4-Chloro-7-nitrobenzofurazan↗