UNIPROT:P50583 - FACTA Search

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Query: UNIPROT:P50583 (asymmetrical)
12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A model is proposed for the structure of stereospecific sites in regulatory proteins. On its basis a possible code is suggested that governs the binding of regulatory proteins at specific control sites on DNA. Stereospecific sites of regulatory proteins are assumed to contain pairs of antiparallel polypeptide chain segments which form a right-hand twisted antiparallel beta-sheet, with single-stranded regions at the ends of the beta-structure. The model predicts that binding reaction between a regulatory protein and double-helical DNA is a cooperative phenomenon and is accompanied by significant structural alteration at the stereospecific site of the protein. Half of hydrogen bonds normally existing in beta-structure are broken upon complex formation with DNA and a new set of hydrogen bonds is formed between polypeptide amide groups and DNA base pairs. In a stereospecific site, one chain (t-chain) is attached through hydrogen bonds to the carbonyl oxygens of pyramides and N3 adenines lying in one DNA strand, while the second polypeptide chain (g chain) is hydrogen bonded to the 2-amino groups of guanine residues lying in the opposite DNA strand. The amide groups serve as specific reaction sites being hydrogen bond acceptors in g-chain and hydrogen bond donors in t-chain. The single-stranded portions of t- and g-chains lying in neighbouring subunits of regulatory protein interact with each other forming deformed beta-sheets. The recognition of regulatory sequences by proteins is based on the structural complementarity between stereospecific sites of regulatory proteins and base pairs sequences at the control sites. An essential feature of these sequences is the asymmetrical distribution of guanine residues between the two DNA strands. The code predicts that there are six fundamental amino acid residues (serine, threonine, asparagine, histidine, glutamine and cysteine) whose sequence in stereospecific site determines the base pair sequence to which a given regulatory protein would bind preferentially. The code states a correspondence between four amino acid residues at the stereospecific site of regulatory protein with the two residues being in t- and g-segments, respectively, and AT(GC) base pair at the control site. It is thus possible to determine which amino acid residues in the repressor and which base pairs in the operator DNA are involved in specific interactions with each other, as exemplified by lac repressor binding to lac operator.
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PMID:[A code governing specific binding of regulatory proteins to DNA and structure of stereospecific sites of regulatory proteins]. 121 4

1. Two mutants of the sodium channel II have been expressed in Xenopus oocytes and have been investigated using the patch-clamp technique. In mutant E387Q the glutamic acid at position 387 has been replaced by glutamine, and in mutant D384N the aspartic acid at position 384 has been replaced by asparagine. 2. Mutant E387Q, previously shown to be resistant to block by tetrodotoxin (Noda et al. 1989), has a single-channel conductance of 4 pS, that can be easily measured only using noise analysis. At variance with the wild-type, the open-channel current-voltage relationship of mutant E387Q is linear over a wide voltage range even under asymmetrical ionic conditions. 3. Mutant D384N has a very low permeability for any of the following ions: Cl-, Na+, K+, Li+, Rb+, Ca2+, Mg2+, NH+4, TMA+, TEA+. However, asymmetric charge movements similar to the gating currents of the Na(+)-selective wild-type are still observed. 4. These results suggest that residues E387 and D384 interact directly with the pathway of the ions permeating the open channel.
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PMID:Single point mutations of the sodium channel drastically reduce the pore permeability without preventing its gating. 166 Mar 94

Acid-base homeostasis depends on glutamine flow from producer organs to those capable of generating bicarbonate. Glutamine oxidation, the prerequisite metabolic transformation, can be expressed by many sites; however, net base generation requires that glutamine flow be directed to a specific organ, the kidney. Normally, glutamine flows from the periphery to the splanchnic bed, providing a major fuel and supporting ureagenesis. Glutamine flow in chronic metabolic acidosis, on the other hand, is rerouted to the kidneys; asymmetrical distribution of NH+4 and HCO3- into the urine and renal vein subserves restoration of alkaline reserves. Clearly, glutamine flows in accordance with physiological demands, yet little is known of the regulatory mechanisms. As a model, chronic metabolic acidosis alters two aspects of this vital flow, its direction and magnitude. Characteristically the direction of flow is away from the splanchnic bed and into the kidneys associated with a marked fall in arterial glutamine concentration, restoring arterial level returns flow to the splanchnic bed sink. Thus glutamine homeostasis is sacrificed to impart direction to interorgan glutamine flow. Although multiple sites contribute to glutamine homeostasis, of great strategic importance is the potent hepatic glutaminase flux activated by portal venous NH+4 fed forward by gut metabolism; local hydrogen ion concentration modulates the effectiveness of this activator. Acute regulation of flow direction can be exerted by the lungs in determining the prevailing pCO2 and cellular acidity; respiratory compensation in chronic acidosis allows the expression of hepatic glutaminase, thereby suppressing arterial glutamine concentration. The enormous magnitude of glutamine flowing from muscle to the kidneys is supported by adaptive increases in glutamine synthetase and mitochondrial glutaminase, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interorgan glutamine flow in metabolic acidosis. 332 41

The contribution of motor and intralaminar thalamic nuclei to the changes of [3H]GABA release evoked in both caudate nuclei (CN) and both substantia nigra (SN) by a unilateral nigral application of muscimol (10(-6) M) was investigated on halothane-anaesthetized cats. Acute lesions were performed on one side of the thalamus at the level of either the ventralis medialis and ventralis lateralis (motor nuclei) or the centralis lateralis and paralamellar zone of the medialis dorsalis (intralaminar nuclei). The release of [3H]GABA neosynthesized from [3H]glutamine was measured by perfusing continuously a [3H]glutamine-enriched physiological medium through a push-pull cannula implanted in the 4 structures under investigation. After two hours of superfusion, muscimol (10(-6) M) was delivered for 60 min through the nigral push-pull cannula implanted ipsilaterally to the thalamic lesion. Evoked changes of [3H]GABA release were analyzed either in motor or intralaminar nuclei lesioned cats and compared to those observed in intact animals. Whatever the localization of the thalamic lesions was, an increased release of [3H]GABA was elicited locally in the SN and distally in the ipsilateral CN as in intact animals, suggesting that the responses induced ipsilaterally did not require nigro-thalamic pathways. On the contrary, in the contralateral CN changes of [3H]GABA release evoked by the nigral muscimol application were reversed by both types of thalamic lesion. Instead of a decreased release of [3H]GABA observed in intact cats, an increased release of [3H]GABA was detected in lesioned animals. In the contralateral SN, the response was reversed only after the intralaminar nuclei lesion. In this situation nigral muscimol application induced a decreased release of [3H]GABA in contrast to the enhanced release observed in intact and motor thalamic lesioned cats. The parallel increased release of [3H]GABA observed in the contralateral CN and SN in motor thalamic nuclei lesioned cats suggests an activation of the striatonigral cells by the nigral muscimol treatment. The asymmetrical changes of [3H]GABA release measured in the contralateral CN and SN in intact and intralaminar nuclei lesioned cats could indicate a presynaptic modulation of the [3H]GABA release acting either at the CN or the SN levels. The possible pathways involved in the interhemispheric transfer of information originating from one SN to the contralateral basal ganglia components are also discussed.
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PMID:In vivo release of [3H]GABA in cat caudate nucleus and substantia nigra. II. Involvement of different thalamic nuclei in the bilateral changes induced by a nigral application of muscimol. 633 70

In halothane anaesthetized cats, a push-pull cannula was implanted into the right caudate nucleus (CN) and in each substantia nigra (SN). The release of [3H]GABA continuously formed from [3H]glutamine was estimated in each structure. Acetylcholine (ACh, 5 x 10(-5) M) added in presence of eserine (5 x 10(-5) M) for 50 min in the right caudate nucleus 2 h after the onset of superfusion with [3H]glutamine, stimulated the [3H]GABA release locally. The effect was biphasic when ACh application was made in the median two-thirds of the structure and it was monophasic and transient when the ACh application was restricted to the lateral part. ACh application in the right caudate nucleus also induced changes in [3H]GABA released in the anterior (pars reticulata) and posterior (pars compacta) parts of both SN. While [3H]GABA release was enhanced in the ipsilateral anterior SN, it was reduced in the contralateral anterior SN. Respective opposite effects were observed in the posterior parts of the ipsi- and contralateral SN. These bilateral asymmetrical changes in [3H]GABA release were not dependent on the site of ACh application in the right caudate nucleus. These results indicate that the facilitation of cholinergic transmission in one caudate nucleus influences in an opposite way the striato-nigral GABA neurones on both sides of the brain.
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PMID:Bilateral asymmetrical changes in the nigral release of [3H]GABA induced by unilateral application of acetylcholine in the cat caudate nucleus. 704 21

D-Glutamate (Glu) was previously shown to block L-Glu uptake and accelerate glutaminase flux in cultured kidney cells [Welbourne, T. C., and D. Chevalier. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E367-E370, 1997]. To test whether D-Glu would be taken up by the intact functioning kidney and effect the same response in vivo, male Sprague-Dawley rats were infused with D-Glu (2.6 mumol/min), and renal uptake of D- and L-Glu was determined from chemical and radiolabeled arteriovenous Glu concentration differences times renal plasma flow. The amount removed was then compared with that amount filtered to obtain the antiluminal contribution. In the controls, L-Glu uptake measured as net removal was 33% of the arterial L-Glu load and not different from that filtered, 27%; however, the unidirectional uptake was actually 58% of the arterial load, indicating that antiluminal uptake contributes at least half to the overall Glu consumption. Surprisingly, the kidneys showed a more avid removal of D-Glu, removing 73% of the arterial load, indicating uptake predominantly across the antiluminal cell surface. Furthermore, uptake of D-Glu was associated with a 55% reduction in L-Glu uptake, with the residual amount taken up equivalent to that filtered; D-Glu did not increase the excretion of the L-isomer. However, elevating plasma L-Glu concentration reduced uptake of the D-isomer, suggesting a shared antiluminal transporter. Thus there is an apparent asymmetrical distribution of the D-Glu transporter. Under these conditions, kidney cortex L-Glu content decreased 44%, whereas net glutamine (Gln) uptake increased sevenfold (170 +/- 89 to 1,311 +/- 219 nmol/min, P < 0.01) and unidirectional uptake nearly threefold (393 +/- 121 to 1,168 +/- 161 nmol/min, P < 0.05); this large Gln consumption was paralleled by an increase in ammonium production so that the ratio of production to consumption approaches 2, consistent with accelerated Gln deamidation and subsequent Glu deamination. These results point to a functional asymmetry (antiluminal vs. luminal) for Glu transporter activity, which potentially plays an important role in modulating Gln metabolism and renal function.
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PMID:Glutamate transport asymmetry in renal glutamine metabolism. 961 46

To elucidate the role of aspartate as a signal molecule in the brain, its localization and those of related amino acids were examined by light and electron microscopic quantitative immunocytochemistry using antibodies specifically recognizing the aldehyde-fixed amino acids. Rat hippocampal slices were incubated at physiological and depolarizing [K+] before glutaraldehyde fixation. At normal [K+], aspartate-like and glutamate-like immunoreactivities were colocalized in nerve terminals forming asymmetrical synapses on spines in stratum radiatum of CA1 and the inner molecular layer of fascia dentata (i.e., excitatory afferents from CA3 and hilus, respectively). During K+ depolarization there was a loss of aspartate and glutamate from these terminals. Simultaneously the immunoreactivities strongly increased in glial cells. These changes were Ca2+-dependent and tetanus toxin-sensitive and did not comprise taurine-like immunoreactivity. Adding glutamine at CSF concentration prevented the loss of aspartate and glutamate and revealed an enhancement of aspartate in the terminals at moderate depolarization. In hippocampi from animals perfused with glutaraldehyde during insulin-induced hypoglycemia (to combine a strong aspartate signal with good ultrastructure) aspartate was colocalized with glutamate in excitatory terminals in stratum radiatum of CA1. The synaptic vesicle-to-cytoplasmic matrix ratios of immunogold particle density were similar for aspartate and glutamate, significantly higher than those observed for glutamine or taurine. Similar results were obtained in normoglycemic animals, although the nerve terminal contents of aspartate were lower. The results indicate that aspartate can be concentrated in synaptic vesicles and subject to sustained exocytotic release from the same nerve endings that contain and release glutamate.
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PMID:Synaptic vesicular localization and exocytosis of L-aspartate in excitatory nerve terminals: a quantitative immunogold analysis in rat hippocampus. 969 1

In patients with malformations of cortical development (MCD), widespread structural abnormalities of the brain have been demonstrated using volumetric MRI, and associated with poor post-surgical outcome in patients with localization-related epilepsy. Proton magnetic resonance spectroscopic imaging (1H-MRSI) studies permit the non-invasive measurement of concentrations of a variety of cerebral metabolites implicated in cerebral structure and function. There is a dearth of quantitative 1H-MRSI studies of MCD. Ten controls and 10 patients with localization-related epilepsy who were found to have MCD on high resolution MRI underwent 1H-MRSI on a 1.5 T GE Signa scanner [TE (echo time) = 30 ms, TR (repetition time) = 3 s]. In all patients, the axial area studied contained lesional and perilesional tissue. In seven unilaterally affected patients, the area studied contained also apparently normal contralateral grey and white matter; in three patients with bilateral but asymmetrical MCD, it contained visually normal and abnormal tissue from both hemispheres. N-acetyl aspartate + N-acetyl aspartyl glutamate (NAA), creatine + phosphocreatine (Cr), choline-containing compounds (Cho), glutamate + glutamine (Glx) and myo-inositol (Ins) were automatically quantified in voxels covering these different regions. Metabolite concentrations were corrected for CSF content and correlated with the grey and white matter of the MRSI voxels. In control subjects, there were significant positive correlations between grey matter content and concentrations of NAA, Glx, Ins and Cr. Compared with a normal range that took grey matter content into account, defined as the control mean +/- 2 SD, all lesions but one showed metabolic abnormalities. The most common abnormality was a decrease in NAA, but findings were heterogeneous and there was increased NAA in one lesion. Perilesional tissue was abnormal in eight patients, with increased NAA in three. Tissue contralateral to the main MCD was abnormal in all three patients with bilateral but asymmetrical MCD, and in six of the seven apparently unilaterally affected patients. Spectroscopic grey and white matter abnormalities in patients with MCD exceeded the apparently focal abnormality shown by MRI, indicating widespread abnormalities of cerebral function.
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PMID:Quantitative short echo time proton magnetic resonance spectroscopic imaging study of malformations of cortical development causing epilepsy. 1115 69

Mutations of the cardiac beta-myosin heavy-chain (beta-MHC) gene cause hypertrophic cardiomyopathy (HCM). Recent genotype-phenotype correlation studies have shown that mutations carry prognostic significance. We studied five unrelated Chinese families with hypertrophic cardiomyopathy. Exons 3-27 and 40 of the beta-MHC gene were screened with both the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method and the cycle sequencing of the PCR products. A previously reported heterozygous mutation Arg719Gln (arginine-->glutamine in codon 719) in exon 19 was found in one family. The proband is a 30-year-old female diagnosed at age of 25 years when she presented with symptoms of chest pain, palpitations, and frequent incidents of dizziness and syncope. A two-dimensional echocardiogram showed moderate asymmetrical septal hypertrophy with left atrial enlargement. There was no obstruction of the left ventricular outflow tract (LVOT). The patient also developed atrial fibrillation. The proband's mother and one of her sisters had similar clinical manifestations and both died suddenly at the age of 38 years. In addition, two silent nucleotide substitutions (ACT63ACC, TTT244TTC) in the cardiac beta-MHC gene were identified in the other four families. These synonymous mutations did not cosegregate with the disease in the families and they were also present in the 60 healthy and age-matched control subjects. Of the five families studied, we did not find any missense mutation in the remaining four families. The missense mutation Arg719Gln found in the Chinese family is associated with a malignant phenotype of severe clinical symptoms and poor survival prognosis. This mutation also causes atrial enlargement and atrial fibrillation. Our study provides further evidence that the mutation, which alters the charge of the myosin heavy chain, is associated with a serious clinical outcome.
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PMID:A malignant phenotype of hypertrophic cardiomyopathy caused by Arg719Gln cardiac beta-myosin heavy-chain mutation in a Chinese family. 1149 78

Brain capillary endothelial cells form the blood-brain barrier. They are connected by extensive tight junctions, and are polarized into luminal (blood-facing) and abluminal (brain-facing) plasma membrane domains. The polar distribution of transport proteins allows for active regulation of brain extracellular fluid. Experiments on isolated membrane vesicles from capillary endothelial cells of bovine brain demonstrated the polar arrangement of amino acid and glucose transporters, and the utility of such arrangements have been proposed. For instance, passive carriers for glutamine and glutamate have been found only in the luminal membrane of blood-brain barrier cells, while Na-dependent secondary active transporters are at the abluminal membrane. This organization could promote the net removal of nitrogen-rich amino acids from brain, and account for the low level of glutamate penetration into the central nervous system. Furthermore, the presence of a gamma-glutamyl cycle at the luminal membrane and Na-dependent amino acid transporters at the abluminal membrane may serve to modulate movement of amino acids from blood-to-brain. Passive carriers facilitate amino acid transport into brain. However, activation of the gamma-glutamyl cycle by increased plasma amino acids is expected to generate oxoproline within the blood-brain barrier. Oxoproline stimulates secondary active amino acid transporters (Systems A and B(o)+) at the abluminal membrane, thereby reducing net influx of amino acids to brain. Finally, passive glucose transporters are present in both the luminal and abluminal membranes of the blood-brain barrier. Interestingly, a high affinity Na-dependent glucose carrier has been described only in the abluminal membrane. This raises the question whether glucose entry may be regulated to some extent. Immunoblotting studies suggest more than one type of passive glucose transporter exist in the blood-brain barrier, each with an asymmetrical distribution. In conclusion, it is now clear that the blood-brain barrier participates in the active regulation of brain extracellular fluid, and that the diverse functions of each plasma membrane domain contributes to these regulatory functions.
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PMID:The complementary membranes forming the blood-brain barrier. 1248 36

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