Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the rabbit, a p59 protein included in the untransformed, non-DNA binding, "8-9S," steroid receptor complexes binds heat shock protein M(r) approximately 90,000 (hsp90). Sequence data [Lebeau, M. C., Massol, N., Herrick, J., Faber, L. E., Renoir, J. M., Radanyi, C. & Baulieu, E. E. (1992) J. Biol. Chem. 267, 4281-4284] and hydrophobic cluster analysis delineate, from the N terminus, two successive domains closely related to the immunosuppressant FK506 binding immunophilin FKBP (FK506 binding protein), consistent with recent purification of the human p56 immunophilin cognate protein by FK506 affinity chromatography [Yem, A. W., Tomasselli, A. G., Heinrikson, R. L., Zurcher-Neely, H., Ruff, V. A., Johnson, R. A. & Deibel, M. R., Jr. (1992) J. Biol. Chem. 267, 2868-2871]. The first FKBP-like domain demonstrates all structural characteristics known to be necessary for immunosuppressant binding and for peptidylprolyl cis-trans isomerase (rotamase) activity. Hence, p59 is a "hsp binding immunophilin" (HBI). It is thus speculated that hsp binding immunophilin may help the assembly/disassembly mechanisms involved in steroid receptor trafficking and activity and participate in the poorly understood hsp90 function. ATP/GTP binding likely occurs within the second FKBP-like domain, near the FK506 binding site on the FKBP template. A third domain detected by the hydrophobic cluster analysis method is distantly structurally related to the two first FKBP-like domains and is followed by the C-terminal part of the protein, which contains a calmodulin binding consensus sequence. Hsp binding immunophilin may be involved in a number of immunological, endocrinological, and chaperone-mediated pathways.
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PMID:An immunophilin that binds M(r) 90,000 heat shock protein: main structural features of a mammalian p59 protein. 163 Nov 18

Calpain, a calcium-dependent, neutral cysteine-protease was purified from the erythrocyte cytosol of subjects having essential hypertension (HTN), sickle cell anaemia, (SCA), or kwashiorkor (KWA). Identical electrophoretic mobility on SDS-polyacrylamide gradient gel, sensitivity to micromolar amounts of Ca2+, absolute requirement for a reducing environment and a high susceptibility to inhibition by leupeptin and thiol-group modifying reagents confirm that calpain preparations from these erythrocytes are equivalent to calpain I. Whereas the extent of calpain activation of erythrocyte membrane Ca2(+)-pumping ATPase of normal subjects was almost equal to that due to calmodulin, calpain activation of the HTN and SCA pump was greater than activation by calmodulin. Like in normal membranes, exogenous calmodulin protected the Ca2(+)-pumping ATPase of these erythrocytes against calpainization; the degree of protection by calmodulin is least in SCA and HTN. Electrophoretic separation of erythrocyte membranes and the purified Ca2(+)-pumping ATPase of HTN, SCA and KWA subjects does not indicate the presence of fragments resulting from the proteolytic action of calpain.
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PMID:Comparative action of calpain on erythrocyte Ca2(+)-pumping ATPase in sickle cell anaemia, essential hypertension and kwashiorkor. 214 87

The elevated calcium content found in red cells from patients with sickle cell anemia may be of pathophysiologic importance in the hemolysis and vasoocclusion which characterize this disorder. Cetiedil, an antisickling agent, has been reported to inhibit the activity of enzymes that are stimulated by the calcium regulatory protein calmodulin. To investigate the mechanism by which cetiedil modifies calcium-mediated erythrocyte function, the effect of the drug on the active transport of calcium into inside-out erythrocyte vesicles was examined and its influence on the activities of phosphodiesterase and Ca-ATPase studied. Cetiedil, in the presence of calmodulin, significantly inhibited calcium transport into inside-out vesicles that were prepared with erythrocytes from normal controls and from patients with sickle cell anemia. However, in the absence of calmodulin, no inhibition was observed. Likewise, cetiedil inhibited calmodulin-stimulated, but not basal, activities of phosphodiesterase and Ca-ATPase. These data, along with previous reports, suggest that cetiedil does not act by lowering the intracellular calcium content. It is, therefore, likely that the beneficial effect of cetiedil is due to its ability to protect the red cell from the deleterious consequences of an elevated concentration of intracellular calcium.
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PMID:Inhibition of erythrocyte calcium transport by cetiedil. 282 42

In normal erythrocytes, a membrane-bound (Ca2+ + Mg2+)-ATPase is stimulated by a soluble activator, calmodulin. Since cells containing Hb S accumulate excessive Ca2+, the defect could lie in either the (Ca2+ + Mg2+)-ATPase or calmodulin. To decide between these two possibilities, we prepared (Ca2+ + Mg2+)-ATPase from erythrocytes of normal (AA), sickle cell trait (AS) and sickle cell disease (SS) individuals. Calmodulin was prepared from haemolysates from AA and SS erythrocytes. The enzyme prepared from SS ghosts had lower specific activity than that from AA membranes. Furthermore, calmodulin from either source did not stimulate the ATPase of SS erythrocytes. Enzyme from AS cells had specific activity similar to that of enzyme prepared from SS membranes. The enzymatic activity of a mixed cell population obtained from an SS patient 8 d following exchange-transfusion was proportional to the per cent Hb A. These results indicate that calmodulin is unable to interact with the enzyme site on the SS membrane. This inability is believed to be due to a specific property of the membrane and not an abnormality of calmodulin itself.
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PMID:The interaction between (Ca2+ + Mg2+)-ATPase and the soluble activator (calmodulin) in erythrocytes containing haemoglobin S. 610 44

To determine whether diminished activity of the Ca++ extrusion pump could account for the high levels of red blood cell (RBC) Ca++ in sickle cell anemia (SS), we measured calmodulin-sensitive Ca++ ATPase activity in normal and SS RBC. Hemolysates prepared with saponin were compared, since such preparations expressed maximum ATPase activities, exceeding isolated membranes or reconstituted systems of membranes plus cytosol, SS RBC hemolysates had greater Ca++ ATPase activity than normal hemolysates; they exhibited higher Mg++ and Na+ + K+ ATPase activities as well. Assays on density (age) fractions of SS and normal red cells demonstrated that all ATPase activities were highest in low density (young) cells, and activities in SS red cells exceeded those in normals in all fractions studied. Thus, when studied under conditions that maximize enzyme activity, Ca++ ATPase activity, like Mg++ and Na+ + K+ ATPase, is actually increased in SS RBC, probably due to the young red cell population present. The elevated Ca++ levels in these cells are more likely due to an increased Ca++ leak or abnormal calcium binding than to defective extrusion by the ATPase pump.
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PMID:Increased Ca++, Mg++, and Na+ + K+ ATPase activities in erythrocytes of sickle cell anemia. 629 75

Intracellular calcium regulates a number of membrane functions in the erythrocyte, including control of shape, membrane lipid composition and cation permeability. Measurement of total red cell calcium has yielded values between 5 and 15 nmol/ml cells, and these low values in part reflect the absence of Ca2+ -containing organelles. Most intracellular Ca2+ is bound and the low cell ionized Ca2+ concentration (approximately 0.2 microM) is maintained by a combination of low membrane permeability and a powerful Ca2+ -pump. This pump has been identified with a (Ca2+ + Mg2+)-stimulated ATPase, and both Ca2+ transport and ATP splitting are stimulated by calmodulin, a low molecular weight protein which binds Ca2+ avidly and activates many Ca2+ -dependent enzymes. Both high and low affinity kinetics for Ca2+ pumping have been demonstrated, depending on the extent of binding of calmodulin to the pump. A stoichiometry of either 1 or 2 Ca2+ ions pumped per ATP molecule split has been shown, and the value may vary with the level of intracellular Ca2+. Phenothiazines, such as chlorpromazine inhibit the Ca2+ -pump by antagonizing the increment in activity produced by calmodulin. The passive inward leak of Ca2+ into erythrocytes can be quantitated by 45Ca2+ uptake into red cells whose Ca2+ -pump has been inhibited. Estimates of the Ca2+ permeability, based on unidirectional influx, yield values many orders of magnitude lower than for nucleated cells. Influx of Ca2+ into human erythrocytes occurs by a facilitated diffusion process, which can be inhibited by phenothiazines and the cinchona alkaloids. Calcium affects many membrane functions including cation permeability, lipid composition and some cytoskeletal interactions which may determine cell shape. Any rise in intracellular Ca2+ activates a specific K+ channel which normally makes little contribution to K+ fluxes. Kinetic studies of this process demonstrate either high or low affinity Ca2+ -activation of K+ efflux, with low affinity of the channel to Ca2+ being the probable state in vivo. Propranolol is the best known activator of Ca2+ -stimulated K+ efflux, although the mechanism of stimulation is unclear. Like other tissues, red cells possess a Ca2+ -activated phosphoinositol phosphodiesterase. Although it has been suggested that the echinocytic shape change induced by Ca2+ is due to the hydrolysis of polyphosphoinositides, it seems more likely that this shape change results from an effect of Ca2+ on the macromolecular interactions of the cytoskeleton. Abnormal Ca2+ permeability may contribute to red cell destruction in a variety of diseases. For example, in sickle cell anemia a large Ca2+ influx occurs when cells are sickled under deoxy conditions, and moreover, the ability of the Ca2+ -pump to extrude the increment of cell Ca2+ is impaired. Thus, red cell Ca2+ is increased 3-7-fold above normal and this may contribute to the short survival of sickle red cells...
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PMID:Calcium ions, drug action and the red cell membrane. 629 89

Red blood cell (RBC) and polymorphonuclear white blood cell (WBC) calmodulin levels were measured in 25 uremic patients on regular hemodialysis. Uremic patients had significantly higher RBC [11.45 +/- 0.66 (+/-SE) fg/cell] and WBC (590.5 +/- 110 fg/cell) calmodulin levels than normal subjects (8.62 +/- 0.37 and 130 +/- 30 fg/cell; P less than 0.05). An extremely high RBC calmodulin level (20.58 fg/cell) was found in a patient with sickle cell anemia. Uremic patients on dialysis for 2 yr or more had lower RBC (10.99 +/- 0.58 fg/cell) and WBC (390 +/- 50 fg/cell) calmodulin levels than those who were on dialysis for less than 2 yr (RBC, 12.30 +/- 1.56 fg/cell; WBC, 943 +/- 256 fg/cell; P less than 0.05). There were no statistically significant differences in calmodulin levels when different subgroups of uremic patients were compared, e.g. patients with diabetes mellitus or those receiving supplemental vitamin D, anabolic steroids, or antihypertensive medications. We conclude that calmodulin levels are elevated in uremic patients on regular hemodialysis.
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PMID:The effects of chronic renal failure and hemodialysis on human red and white cell calmodulin levels. 672 5

We have postulated that the sickle erythrocyte becomes membrane damaged at least partly due to excessive accumulation of calcium and then to excessive calmodulin activation (42). We have found that zinc therapy in sickle cell anemia improves the membrane status of the sickle cells (53). We have some evidence that zinc is an inhibitor of calmodulin functions, and postulate that zinc's beneficial membrane effect in sickle cell anemia is due to its calmodulin inhibitory properties (42). This reasoning opens the therapeutic door to other calmodulin inhibitors, such as the phenothiazines, which coincidentally, had already been shown to have antisickling properties years ago (59). The phenothiazines "expand" the red cell membrane, a property shown by Seeman (60) to be shared with a wide variety of drugs. If membrane expansion is due to calmodulin inhibition as we believe (42), then all of the membrane expanding drugs share the potential for antisickling properties. These ideas, if correct, rationalize under one mechanism, the reported antisickling properties of a diverse group of drugs, including zinc, procaine, the phenothiazines and most recently, ceteidil. If these possible new insights into the mechanism of antisickling membrane therapy, namely CAC inhibition in sickle cells, lead to a rational and successful approach to therapy in sickle cell anemia, it will be because of the precedent provided by understanding the action of zinc.
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PMID:Molecular mechanisms of zinc action on cells. 700 58

1. Three phenothiazines with similar structure; chlorpromazine (CPZ), triflupromazine (TFPZ), and trifluoperazine (TFP), were compared for the potency of swelling of normal red cells and antisickling effect of red cell from patients with sickle cell disease. 2. Normal erythrocytes treated with the phenothiazines became swollen within 60 min, and the percent increase in mean cell volume (MCV) was dose-dependent and varied according to the agent used. 3. The cell swelling was hematocrit-dependent, and pH-dependent. A greater swelling potency was seen at lower hematocrits and higher pH values. 4. The swelling was also dependent on the pKa values of these chemicals. TFP with the lowest pKa induced the highest degree of swelling while CPZ with the highest pKa induced the lowest. 5. The un-ionized fraction of the phenothiazines at a given pH was directly related to potency of the swelling. 6. The cell swelling was directly related to the binding affinities of the phenothiazines to calmodulin. 7. The antisickling effect of these compounds using sickle red cells, numerically estimated by an automated image analysis system, was found in the same order as that of swelling potency: TFP > TFPR > CPZ.
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PMID:Comparative studies of phenothiazine derivatives for their effects on swelling of normal and sickle erythrocytes. 790 Nov 17

This review discusses the Ca2+-activated K+ channels of intermediate conductance (IK channels), and their historical discovery in erythrocytes, their classical biophysical characteristics, physiological function, molecular biology as well as their role as possible molecular targets for pharmacological intervention in various diseases. The first described Ca2+-activated K+ channel ever - the so-called Gard6s channel from human erythrocytes--is an IK channel. The "I" denominates the intermediate conductance that distinguishes the IK channels from the related Ca2+-activated K+ channels of small (SK) or large (BK) conductance. The recent cloning of the human IK channel gene (KCNN4) enabled a detailed mapping of the expression in various tissues. IK channel expression is found predominantly in cells of the blood, in epithelia and endothelia. An important physiological role of IK channels is to set the membrane potential at fairly negative values and thereby to build up large electrical gradients for the passive transport of ions such as Cl- efflux driving water and Na+ secretion from epithelia, and Ca2+ influx controlling T-lymphocyte proliferation. The molecular cloning of IK and SK channels has revealed that both channels gain their Ca2+-sensitivity from tightly bound calmodulin (CaM). The IK channel is potently blocked by the scorpion toxin charybdotoxin (ChTx) and the antimycotic clotrimazole (CLT). CLT has been in clinical trials for the treatment of sickle cell disease, diarrhea and ameliorates the symptoms of rheumatoid arthritis. However, inhibition of cytochrome P450 enzymes by CLT limits its therapeutic value, but new drug candidates are entering the stage. It is discussed whether pharmacological modulation of IK channels may be beneficial in sickle cell anemia, cystic fibrosis, secretory diarrhea, craft-versus-host disease and autoimmune diseases.
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PMID:The Ca2+-activated K+ channel of intermediate conductance: a molecular target for novel treatments? 1173 39


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