Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alkyl and arylalkyl derivatives of the dopamine (DA) D2 antagonist spiperone were prepared and characterized chemically and pharmacologically. They included the N-methyl, N-phenethyl (NPS), and N-p-aminophenethyl (NAPS) derivatives, as well as the alkylating isothiocyanato (NIPS), bromacetamido, and ethylfumaramido p-substituted N-phenethylspiperones. These compounds showed high lipophilicity (log P up to 6.0 with NIPS), as well as very high in vitro D2 affinity (Ki = 35-280 pM) and D2 versus D1 selectivity (540-9000-fold) in radioreceptor assays with corpus striatum of rat brain. Of the alkylating series, NIPS showed the highest D2 affinity (57 pM) and D2 versus D1 selectivity (2040-fold) and so was selected for further evaluation. NPS, NAPS, and NIPS showed little or no affinity for 34 non-DA binding sites defined by radioligand assays for monoamine, amino acid, and peptide neurotransmitters, ion channels, peptide growth factors, and transmission mediators but did show low alpha 2 and moderate alpha 1 and 5-hydroxytryptamine (5-HT2) affinity with rat forebrain tissue in vitro; NIPS showed a marked gain in D2 versus 5-HT2 selectivity, compared with spiperone (1520- versus 26-fold). Systemic injections of NIPS induced marked decreases in rat striatal D2 binding sites 24 hr later, with little effect on D1, 5-HT2, or alpha 1 sites; NIPS and NAPS lowered apparent Bmax values at D2 receptors with little change in ligand affinity, ex vivo as well as in vitro. NPS, NAPS, and NIPS all induced dose-dependent lowering of D2 binding ex vivo (ID50 = 1-9 mumol/kg, intraperitoneally) and blocked the behavioral effects of the DA agonist apomorphine (0.9 mumol/kg) potently (ID50 = 0.3-0.5 mumol/kg) at 24 hr. Recovery from these anti-DA actions required about 1 week after equimolar (15 mumol/kg) and similarly effective doses of NPS and NAPS, as well as NIPS. Thus, highly selective and avidly bound lipophilic D2 affinity ligands with similarly avid in vitro and prolonged in vivo anti-DA activities can be derived from N-phenethylspiperones with or without an alkylating moiety present. Such affinity ligands may represent useful additions to previously used, generally less selective, D2 affinity ligands.
Mol Pharmacol 1992 Nov
PMID:Prolonged D2 antidopaminergic activity of alkylating and nonalkylating derivatives of spiperone in rat brain. 143 53

NPS(o-nitrophenyl sulfenyl)-ACTH stimulated steroidogenesis in Y1 cells to the same maximum level as did ACTH, but with a 60-fold lower potency than the native hormone. NPS-ACTH also stimulated the extracellular accumulation of cAMP in Y1 cells with lower potency than the unmodified hormone. The amount of cAMP accumulated in the presence of NPS-ACTH approached 75% of the maximum with ACTH. In Y1 plasma membranes, NPS-ACTH was a partial agonist of adenylate cyclase activity, witn an efficacy dependent upon the type of guanyl nucleotide present. The steroidogenic responses of two Y1(Kin) mutants and two Y1(Cyc) mutants to NPS-ACTH paralleled their responses to ACTH and reflected closely their defects in cAMP-dependent protein kinase and ACTH-sensitive adenylate cyclase activity. These data imply an obligatory role for adenylate cyclase and cAMP-dependent protein kinase activities in stimulation of steroidogenesis in Y1 cells by NPA-ACTH.
Mol Cell Endocrinol 1980 Mar
PMID:Responses of Y1 adrenocortical tumor cells to o-nitrophenyl sulfenyl ACTH. 624 80

The Ca2+ receptor is a G protein-coupled receptor that enables parathyroid cells and certain other cells in the body to respond to changes in the concentration of extracellular Ca2+. In this study, two novel phenylalkylamine compounds, NPS 467 and NPS 568, were examined for effects on Xenopus laevis oocytes expressing the bovine or human parathyroid Ca2+ receptors. Increases in chloride current (ICl) were elicited in oocytes expressing the bovine Ca2+ receptor when the extracellular Ca2+ concentration was raised above 1.5 mM, whereas Ca2+ concentrations > 3 mM were generally necessary to elicit responses in oocytes expressing the human Ca2+ receptor. NPS 467 and NPS 568 potentiated the activation of ICl by extracellular Ca2+ in oocytes expressing either Ca2+ receptor homolog, and this resulted in a leftward shift of the Ca2+ concentration-response curve. Neither compound was active in the absence of extracellular Ca2+. Certain inorganic and organic cations known to activate the Ca2+ receptor were substituted for elevated levels of extracellular Ca2+ to increase ICl and the effects of these agonists were also potentiated by NPS 568 or NPS 467. The effects of NPS 568 were stereoselective and the R-enantiomer was about 10-fold more potent than the corresponding S-enantiomer. Neither NPS 467 nor 568 affected ICl in water-injected oocytes or in oocytes expressing the substance K receptor or the metabotropic glutamate receptor 1a. These results provide compelling evidence that NPS 467 and NPS 568 act directly upon the parathyroid Ca2+ receptor to increase its sensitivity to activation by extracellular Ca2+. This activity suggests that these compounds are positive allosteric modulators of the Ca2+ receptor. As such, these compounds define a new class of pharmacological agents with potent and selective actions on the Ca2+ receptor.
Mol Pharmacol 1998 Jun
PMID:Allosteric activation of the Ca2+ receptor expressed in Xenopus laevis oocytes by NPS 467 or NPS 568. 961 12

Nail-patella syndrome (NPS) is an inherited developmental disorder most commonly involving maldevelopment of the fingernails, kneecaps and elbow joints. NPS exhibits wide variation in phenotypic expression within and among families with respect to these features. Other skeletal abnormalities such as hip dislocation and club foot have also been reported in some individuals with NPS. There is an association between NPS and renal disease, and between NPS and open-angle glaucoma (OAG), but it is not known whether mutations in a single gene cause the observed skeletal, renal and ophthalmic abnormalities. Recently, LMX1B , a transcription factor of the LIM-homeodomain type with homologs that are important for limb development in vertebrates, was mapped to the same general location as NPS at 9q34. We sequenced a large segment of LMX1B from the genomic DNA of probands from four families with NPS and OAG, and identified four mutations: two stop codons, a deletion causing a frameshift and a missense mutation in a functionally important residue. The presence of these putative loss-of-function mutations in the DNA of individuals with NPS indicates that haploinsufficiency of LMX1B underlies this disorder. These findings help to explain the high degree of variability in the NPS phenotype, and suggest that the skeletal defects in NPS are a result of the diminished dorsoventral patterning activity of LMX1B protein during limb development. The results further suggest that the NPS and OAG phenotypes in the families studied result from mutations in a single gene, LMX1B.
Hum Mol Genet 1998 Jul
PMID:Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome. 961 65

Protein S from Myxococcus xanthus is a member of the beta gamma-crystallin superfamily. Its N and C-terminal domains (NPS and CPS, respectively) show a high degree of structural similarity and possess the capacity to bind two calcium ions per domain. For NPS, their positions were determined by X-ray diffraction at 1.8 A resolution, making use of molecular replacement with the NMR structure as search model. The overall topology of NPS is found to be practically the same as in complete protein S. In natural protein S, the domains fold independently, with a significant increase in stability and cooperativity of folding in the presence of Ca2+. The recombinant isolated domains are stable monomers which do not show any tendency to combine to "nicked" full-length protein S. In order to investigate the stability and folding of natural protein S and its isolated domains, spectroscopic techniques were applied, measuring the reversible urea and temperature-induced unfolding transitions at varying pH. The increment of Ca2+ to the free energy of stabilization amounts to -10 and -5 kJ/mol for NPS and CPS, respectively. For both NPS and CPS, in the absence and in the presence of 3 mM CaCl2, the two-state model is valid. Comparing DeltaGU-->N for CPS (-21 kJ/mol at pH 7, liganded with Ca2+) with its increment in the intact two-domain protein, the stability of the isolated domain turns out to be decreased in a pH-dependent manner. In contrast, the stability of Ca2+-loaded NPS (DeltaGU-->N=-31 kJ/mol, pH 7) is nearly unchanged down to pH 2 where Ca2+ is released (DeltaGU-->N=-26 kJ/mol, pH 2). In intact protein S, the N-terminal domain is destabilized relative to NPS. Evidently, apart from Ca2+ binding, well-defined domain interactions contribute significantly to the overall stability of intact protein S.
J Mol Biol 1999 Mar 12
PMID:The domains of protein S from Myxococcus xanthus: structure, stability and interactions. 1006 14

The betagamma-crystallin superfamily consists of a class of homologous two-domain proteins with Greek-key fold. Protein S, a Ca(2+)-binding spore-coat protein from the soil bacterium Myxococcus xanthus exhibits a high degree of sequential and structural homology with gammaB-crystallin from the vertebrate eye lens. In contrast to gammaB-crystallin, which undergoes irreversible aggregation upon thermal unfolding, protein S folds reversibly and may therefore serve as a model in the investigation of the thermodynamic stability of the eye-lens crystallins. The thermal denaturation of recombinant protein S (PS) and its isolated domains was studied by differential scanning calorimetry in the absence and in the presence of Ca(2+) at varying pH. Ca(2+)-binding leads to a stabilization of PS and its domains and increases the cooperativity of their equilibrium unfolding transitions. The isolated N-terminal and C-terminal domains (NPS and CPS) obey the two-state model, independent of the pH and Ca(2+)-binding; in the case of PS, under all conditions, an equilibrium intermediate is populated. The first transition of PS may be assigned to the denaturation of the C-terminal domain and the loss of domain interactions, whereas the second one coincides with the denaturation of the isolated N-terminal domain. At pH 7.0, in the presence of Ca(2+), where PS exhibits maximal stability, the domain interactions at 20 degrees C contribute 20 kJ/mol to the overall stability of the intact protein.
J Mol Biol 1999 Oct 15
PMID:Calorimetric analysis of the Ca(2+)-binding betagamma-crystallin homolog protein S from Myxococcus xanthus: intrinsic stability and mutual stabilization of domains. 1051 20

Glioblastoma cells exhibit several forms of sensitivity to extracellular calcium (Ca(o)) that might be conferred by the Ca(o)-sensing receptor (CaR) that is intimately involved in the maintenance of Ca(o) homeostasis by various cell types. This receptor is expressed in human glioblastoma cell line, U87, and here we show that CaR activators stimulate a Ca(2+)-activated potassium (K(+)) channel (CAKC) with a conductance of 140 pS. The responses to CaR activators, however, were blunted in U87 cells transfected with a CaR bearing an inactivating mutation (R185Q) that has previously been shown to exert a dominant negative (DN) action on the wild type receptor. Raising Ca(o) from 0.75 to 2.0 mM or addition of a polycationic CaR agonist, each activated CAKC in nontransfected wild type and empty vector-transfected U87 cells, while they had little or no effect on channel activity in cells expressing the DN CaR (DN-CaR cells). In nontransfected wild type and empty vector-transfected cells, the specific 'calcimimetic' CaR activator, NPS R-467, stimulated the channel, while its less active stereoisomer, NPS S-467, did not. In DN-CaR cells, in contrast, NPS R-467, had no effect on channel activity, suggesting defective coupling of the CaR to this ion channel. CaR-mediated stimulation of these K(+) channels could lead to membrane repolarization and related changes in cellular function under normal conditions. Since the R185Q mutation in the CaR produces a more severe phenotype in humans than most inactivating mutations of this receptor, some of its clinical consequences could potentially result from abnormal CaR-dependent channel functioning.
Brain Res Mol Brain Res 2000 Sep 15
PMID:Defective extracellular calcium (Ca(o))-sensing receptor (CaR)-mediated stimulation of a Ca(2+)-activated potassium channel in glioblastoma cells transfected with a dominant negative CaR. 1103 50

The secretion of parathyroid hormone (PTH) and calcitonin (CT) in mammals are both tightly regulated by the prevailing levels of extracellular ionic calcium (Ca(2+)). And, it is now widely recognized that both of these Ca(2+) effects are mediated exclusively through a seven transmembrane calcium sensing receptor or CaR. As in the case of PTH and CT, the secretion of stanniocalcin (STC) in fish is tightly regulated by the levels of extracellular Ca(2+). Fish STC functions as an anti-hypercalcemic hormone such that a rise in extracellular Ca(2+) above the physiological set-point of approximately 1.2 mM provokes an immediate secretory response. Whether or not Ca(2+)-regulated STC secretion in fishes is mediated by similar type of receptor has never been addressed. Here, we have found that Ca(2+)-stimulated STC secretion in salmon is mimicked by CaR mimetics, pharmacological agents that increase the sensitivity of the CaR to calcium. NPS 467, a small organic molecule that acts as a positive allosteric modulator of the CaR and alters calciotropic hormone secretion in mammals, was examined for effects on serum levels of STC in trout. The IP administration of NPS R-467 had time and dose-dependent stimulatory effects on STC secretion that were indistinguishable from those of Ca(2+) loading. The effects of NPS 467 were stereospecific and had no effects on serum CT. NPS 467 induced STC release was also manifested by a downstream physiological response; the inhibition of gill calcium transport. A cDNA clone was amplified from a fish corpuscle of Stannius cDNA library with high homology to the human CaR. RT-PCR revealed that this transcript was also present in gill, kidney, pancreas, brain, muscle and spleen. These findings suggest that Ca(2+)-stimulated STC secretion in fishes is mediated by a calcium ion-sensing receptor similar to that in mammals.
Mol Cell Endocrinol 2002 Jan 15
PMID:Evidence for calcium-sensing receptor mediated stanniocalcin secretion in fish. 1185 Jan 27

The Ca(2+) receptor on the surface of parathyroid cells is the primary molecular entity regulating secretion of parathyroid hormone (PTH). Because of this, it is a particularly appealing target for new drugs intended to increase or decrease circulating levels of PTH. Calcilytic compounds are Ca(2+) receptor antagonists which increase the secretion of PTH. The first reported calcilytic compound was NPS 2143, an orally active molecule which elicits rapid, 3- to 4-fold increases in circulating levels of PTH. These rapid changes in plasma PTH levels are sufficient to increase bone turnover in ovariectomized, osteopenic rats. When administered together with an antiresorptive agent (estradiol), NPS 2143 causes an increase in trabecular bone volume and bone mineral density in osteopenic rats. The magnitude of these changes are far in excess of those caused by estradiol alone and are comparable with those achieved by daily administration of PTH or a peptide analog. These anabolic effects of NPS 2143 on bone are not associated with hyperplasia of the parathyroid glands. Calcilytic compounds can increase endogenous levels of circulating PTH to an extent that stimulates new bone formation. Such compounds could replace the use of exogenous PTH or its peptide fragments in treating osteoporosis.
J Mol Endocrinol 2002 Aug
PMID:The search for calcium receptor antagonists (calcilytics). 1220 Feb 26

Plasmid pB4 is a conjugative antibiotic resistance plasmid, originally isolated from a microbial community growing in activated sludge, by means of an exogenous isolation method with Pseudomonas sp. B13 as recipient. We have determined the complete nucleotide sequence of pB4. The plasmid is 79,370 bp long and contains at least 81 complete coding regions. A suite of coding regions predicted to be involved in plasmid replication, plasmid maintenance, and conjugative transfer revealed significant similarity to the IncP-1beta backbone of R751. Four resistance gene regions comprising mobile genetic elements are inserted in the IncP-1beta backbone of pB4. The modular 'gene load' of pB4 includes (1) the novel transposon Tn 5719 containing genes characteristic of chromate resistance determinants, (2) the transposon Tn 5393c carrying the widespread streptomycin resistance gene pair strA-strB, (3) the beta-lactam antibiotic resistance gene bla(NPS-1) flanked by highly conserved sequences characteristic of integrons, and (4) a tripartite antibiotic resistance determinant comprising an efflux protein of the resistance-nodulation-division (RND) family, a periplasmic membrane fusion protein (MFP), and an outer membrane factor (OMF). The components of the RND-MFP-OMF efflux system showed the highest similarity to the products of the mexCD-oprJ determinant from the Pseudomonas aeruginosa chromosome. Functional analysis of the cloned resistance region from pB4 in Pseudomonas sp. B13 indicated that the RND-MFP-OMF efflux system conferred high-level resistance to erythromycin and roxithromycin resistance on the host strain. This is the first example of an RND-MFP-OMF-type antibiotic resistance determinant to be found in a plasmid genome. The global genetic organization of pB4 implies that its gene load might be disseminated between bacteria in different habitats by the combined action of the conjugation apparatus and the mobility of its component elements.
Mol Genet Genomics 2003 Feb
PMID:The 79,370-bp conjugative plasmid pB4 consists of an IncP-1beta backbone loaded with a chromate resistance transposon, the strA-strB streptomycin resistance gene pair, the oxacillinase gene bla(NPS-1), and a tripartite antibiotic efflux system of the resistance-nodulation-division family. 1258 32


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