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PubMed1986

Peptide fractionation by high-performance liquid chromatography on an Asahipak GS-320 column: application to determination of the disulfide pairings in ribonuclease F1.

High-performance liquid chromatography on an Asahipak GS-320 column using isocratic elution with 0.1 M acetic acid has proven effective for fractionation of peptides of molecular weights lower than 3000. This technique enabled the separation of the peptides derived from digestion of native ribonuclease F1 by trypsin and chymotrypsin in combination with conventional gel filtration through Sephadex G-25 and reversed-phase HPLC. Amino acid analysis of the cystine-containing peptides thus obtained revealed the disulfide linkages Cys-6-Cys-102 and Cys-24-Cys-84 in this protein. The behavior of a number of peptides in the HPLC on an Asahipak GS-320 column is described and the separation mechanism is discussed.

Amino Acids↗

PubMed1992

A method for evaluating the effects of ligands upon Gs protein-coupled receptors using a recombinant melanophore-based bioassay.

As an increasing number of medically important receptors that couple to stimulatory guanine nucleotide (Gs) proteins are isolated and cloned, there is an equally escalating need for methods to rapidly and reproducibly evaluate potential ligands for their properties as agonists or antagonists. Recently, a bioassay that can quickly and accurately determine the effects of numerous chemicals on a beta 1-like adrenergic receptor (AR) endogenous to melanophores derived from Xenopus laevis was developed. Here, the general utility of the melanophore-based pigment dispersion assay is demonstrated by employing it to evaluate the effects of drugs on a human beta 2 AR. Melanophores were both transiently and stably transfected with a plasmid encoding a beta 2 AR. Stimulation of recombinant cells expressing the beta 2 AR, but not wild-type cells, with beta 2-selective agonists induced pigment dispersion and concomitant elevations in intracellular cAMP. Using a microtiter plate reader, it was straightforward to construct reproducible dose-response curves and rapidly determine rank-order potency and EC50 and IC50 values for agonists and antagonists, respectively. The demonstration of functional expression of a human beta 2 AR in the melanophore-based bioassay suggests that the system may be used for the rapid pharmacological characterization of ligands upon any specific Gs-linked receptor for which a cDNA clone is available.

Animals↗

PubMed1991

Specific activation of Gs by synthetic peptides corresponding to an intracellular loop of the beta-adrenergic receptor.

Peptides corresponding to the amino acid sequence of the hamster beta 2-adrenergic receptor (beta 2AR) were synthesized and their ability to activate purified G-proteins determined. Two peptides, comprising the N- and C-terminal 15 amino acids of the putative third intracellular loop region of the beta 2AR were found to activate the G-protein Gs but not to activate a preparation of Gi/Go. Other peptides corresponding to the internal portions of this loop and the C-terminal tail region failed to activate either G-protein. The presence of phospholipid vesicles was required for this activation. The observation that peptides with sequences corresponding to the ends of the third intracellular loop of the beta AR can specifically activate Gs confirms the results of previous mutagenesis studies on the receptor and demonstrates that the secondary structure conferred by the amino acid sequences in these regions is sufficient for the activation of G-proteins.

Amino Acid Sequence↗

PubMed1994

Activated Gs alpha but not Gi alpha prevents the thermal inactivation of adenylyl cyclase in plasma membranes derived from S49 lymphoma cells.

The thermal inactivation of adenylyl cyclase was studied in plasma membranes isolated from wild-type and the mutant cell strain cyc- of S49 lymphoma. The half-life of adenylyl cyclase activity at 30 degrees C was decreased from 14.2 min to 3.4 min by the presence of detergents. ATP as well as forskolin prevented the adenylyl cyclase inactivation in a dose-response manner independent of the utilized type of cell membranes. Activation of G-proteins by GTP gamma S or by AlF-4 in wild-type membranes but not in cyc- membranes partially prevented adenylyl cyclase inactivation. Adenylyl cyclase activity in cyc- membranes was preserved in the presence of GTP gamma S or AlF-4 from the observed detergent-induced inactivation by complementation of these membranes with an extract from wild-type membranes. ADP-ribosylation of Gi alpha in cyc- membranes did not influence the kinetics of the inactivation process of adenylyl cyclase, whereas ADP-ribosylated Gs alpha protein protected adenylyl cyclase more effectively than non-ribosylated Gs alpha in wild-type plasma membranes when GTP was used as an activator.

Adenosine Triphosphate↗

PubMed1989

Cholera toxin enhances ischemia-induced arrhythmias in the isolated rat heart--involvement of a guanine nucleotide binding protein (Gs).

Cholera toxin (CTX) at a dose, which disturbed the intestinal functions, was administered into the rat via the tail vein. At 3 hr after injection, the heart was removed and perfused or subject to global ischemia in the Langendorff isolated heart preparation. Electrocardiogram (ECG) was recorded throughout the experiment. The myocardial cAMP content was measured in the intact non-ischemic heart, and in the isolated ischemic heart at 2.5, 5 and 10 min after ischemia. It was found that the incidence and severity of malignant ventricular arrhythmias including ventricular tachycardia (VT) and ventricular fibrillation (VF) was significantly increased during ischemia in the CTX treated group. The cAMP content was also significantly increased in the CTX treated group in both intact non-ischemic and ischemic hearts, indicating an activation of the guanine nucleotide regulatory protein (Gs). The results of the present study provide evidence that activation of Gs during ischemia may also contribute to the genesis of arrhythmia.

Animals↗

PubMed1994

Antibodies directed against alpha subunits of Gi, Gx/z, GO and GS transducer proteins reduced the morphine withdrawal syndrome in mice.

The effect of intracerebroventricular (i.c.v.) injection of antibodies directed against alpha subunits of Gi, Gx/z, GO and GS regulatory proteins on morphine dependence was analyzed in mice. Animals were rendered tolerant-dependent by subcutaneous (s.c.) implantation of an oily suspension (10 ml/kg) containing 0.1 g/ml of morphine. After 72 h of chronic morphine, 1 mg/kg s.c. naloxone precipitated the withdrawal syndrome. The anti Gi2 alpha, Gx/z alpha, GO1/2 alpha and GS alpha antibodies given 24 h before starting the chronic morphine treatment, reduced the number of jumps recorded. An effect also produced by pertussis toxin, agent impairing the function of Gi/GO transducer proteins. The antibodies injected 24 h before the naloxone challenge reduced the number of animals presenting the jumping behavior, as well as the average number of jumps. This was observed for antibodies against alpha subunits of Gi, Gx/z and GO1/2 proteins. Thus, i.c.v. injection of anti G alpha antibodies by reducing the function of opioid and non-opioid receptors alleviated the morphine withdrawal syndrome.

Analgesia↗

PubMed1983

Multiple origins of the complementary defective genomes of RF and origin proximal sequences of GS, two human papovavirus isolates.

It has previously been shown that the genome of RF virus, a variant of the human papovavirus, BK, consists of two DNA species, one (R1a) with a deletion corresponding to the early and the other (R2) with a deletion corresponding to the late region of BKV (A. Pater, M.M. Pater, and G. di Mayorca (1980). J. Virol. 36, 480-487; A. Pater, M. M. Pater, R. M. Dougherty, and G. di Mayorca (1981a). Virology 113, 86-94). In this report transfection experiments are used to show that these DNA species are individually defective for infection and that both DNA molecules are required simultaneously for the infection of human embryonic kidney (HEK) cells. DNA fragments containing the origin of replication in each of the DNA species are analyzed to show that R1a contains three and R2 contains two origins of replication. In addition, several changes in the repeat region proximal to the origin of replication are observed. The changes involve deletions and insertions. Examination of the deleted junctions most often reveals involvement of short stretches of repeated sequences (hot spots) in recombination. Another observed change is the insertion into R2 of a 63-bp sequence which contains no homology to either BK or SV40 DNA. This insertion is into the late-promoter region of this late-region coding DNA and appears to replace a poor "TATA" box in BK wild type with a better TATA box with the correct spacing from the "CAAT" box. A 304-bp fragment containing the origin of replication, early and late promoters, and the repeat units proximal to the origin of replication of GS, another variant of human BKV papovaviruses has also been sequenced. Several rearrangements, including deletions and insertions in the repeat region, are observed. Moreover, when homologous regions of this virus are compared to that of BKV, five base changes are detected, one of which is in the 23-bp origin region. This base change gives this 23-bp palindrome of GS a perfect two-fold rotational symmetry.

Cell Line↗

PubMed1992

Characterization of human herpesvirus-6(U1102) and (GS) gp112 and identification of the Z29-specified homolog.

Monoclonal antibody 2D10 (MAb 2D10) raised toward human herpesvirus-6(U1102) [HHV6(U1102)] immunoprecipitated three glycosylated peptides, M(r) 112,000, 64,000, and 58,000, designated as gp112 from U1102-infected lymphocytes. Pulse-chase experiments suggest that the M(r) 64,000 and 58,000 polypeptides are very likely generated by post-translational cleavage of the M(r) 112,000 polypeptide. MAb 2D10 neutralized virion infectivity in the presence of complement, suggesting that gp112 is located in the virion envelope. MAb 2D10 did not prevent the appearance of HHV6-specific cytopathic effect. MAb 2D10 was reactive with denatured gp112 in immunoblots. HHV6 isolates form two clusters (Schimer, Wyatt, Yamanishi, Rodriguez, and Frenkel, Proc. Natl. Acad. Sci. USA 88, 5922; Ablashi, Balachandran, Josephs, Hung, Krtueger, Kramarsky, Salahuddin, and Gallo, Virology 184, 545). MAb 2D10 reacted by immunofluorescence and immunoprecipitation with the prototypes of each cluster, GS and Z29. Whereas the proteins immunoprecipitated by MAb 2D10 from GS-infected lymphocytes had an electrophoretic pattern very similar to that of U1102 gp112, the homologous glycoprotein immunoprecipitated from Z29-infected lymphocytes consisted of three polypeptides with M(r) 102,000, 59,000, and 50,000. The data suggest a variation among HHV6 isolates as far as this glycoprotein is concerned.

Animals↗

PubMed1992

Chronic elevation of cAMP levels induces changes in the adenylate cyclase system, opiate receptor sensitivity and levels of Gs-mRNA in cultured neurons.

Neurons in primary culture were treated (5 days) with the adenylate cyclase stimulator 10(-5) M forskolin. The basal adenylate cyclase was decreased by 57%. The acute stimulatory effect of forskolin was down-regulated by 48%. The inhibitory effects of the 3 opiate receptor agonists (mu, delta and kappa) were partly abolished. The abundance of mRNA encoding the stimulatory G-protein (Gs) was decreased prominently. The data indicate that the cAMP system in neuronal cells in primary culture is under dynamic regulation, possibly including altered Gs-protein gene expression. Furthermore, long-term forskolin treatment might induce increased proliferation in susceptible neural blast cells.

Adenylyl Cyclases↗

PubMed1991

Polylysine activates membrane-bound adenylyl cyclase from Xenopus laevis oocytes through the Gs transducing protein.

1. The activity of the adenylyl cyclase found in the membranes of Xenopus laevis can be affected by polylysine and other polycations. 2. The activity of the catalytic subunit measured with forskolin is inhibited by polylysine and polyarginine at concentrations above 10 microM and by spermine above 3 mM. 3. The adenylyl cyclase activity stimulated by GTP-gamma-S or F- through the stimulatory G protein (Gs) can be increased by polylysine, polyornithine and spermine but not by polyarginine. 4. Polylysine stimulation of Gs dependent activity is due to the increase in the apparent affinity for GTP-gamma-S and to a lowering of the requirement for Mg2+ concentration.

Adenylyl Cyclases↗

PubMed1988

Sequence analysis of the gtfC gene from Streptococcus mutans GS-5.

The nucleotide sequence of the gtfC gene, which codes for glucosyltransferase synthesizing both water-soluble and water-insoluble glucans, and its flanking regions from Streptococcus mutans GS-5, was determined. Although the gtfC gene (4218 bp) is preceded by a Shine-Dalgarno (SD) sequence, a promoter-like sequence for this gene could not be identified. The gtfC gene product composed of 1375 amino acid residues (approx. 153 kDa) is generally hydrophilic with three small hydrophobic domains. Two direct repeating units were found near the C terminus of the peptide. The gtfC gene has extensive homology with the previously sequenced gtfB gene. The homologous regions correspond to the signal sequence, an internal region, and the direct repeating units of the peptide. An open reading frame preceded by an SD sequence and followed by an inverted repeat sequence was found immediately downstream from the gtfC gene. The combined sequences of the gtfB and gtfC genes as well as flanking regions suggest that the two gtf genes and the small downstream coding region could be coordinately expressed within an operon. The possible evolution of the gtfC gene in S. mutans GS-5 is also discussed.

Amino Acid Sequence↗

PubMed1996

Ultrastructural localization of G-protein GS in the lateral wall of the guinea pig cochlear duct.

Immunocytochemical localization of a GTP-binding protein, Gs, in the various cells of the lateral wall of guinea pig cochlear duct was investigated using a post-embedding immunogold method with antibody raised against a synthetic decapeptide (RMHLRQYELL) encoding the C-terminus of the alpha-subunit of Gs. In the stria vascularis, labeling was observed on the basolateral membrane infoldings of marginal cells, on the juxtaposed membrane of intermediate cells, and on the cell membrane of basal cell. In contrast, no significant labeling was observed on the luminal membrane of marginal cells. Immunoreactivity also was detected on the cell membranes of various other cells. These include spiral prominence epithelial cells, fibrocytes of spiral ligament, external sulcus cells, and epithelial and mesothelial cells of Reissner's membrane. Adenylylcyclase has been functionally implicated in some of the cell types with membranes labeled in this study. The significance of these findings is briefly discussed.

Adenylyl Cyclases↗

PubMed1991

G protein Gs alpha (GNAS 1), the probable candidate gene for Albright hereditary osteodystrophy, is assigned to human chromosome 20q12-q13.2.

Guanine nucleotide-binding proteins, also known as G proteins, mediate intracellular responses to a wide variety of extracellular stimuli. A variety of genes that specify the synthesis of the components of guanine nucleotide proteins have been identified. One of these proteins, termed Gs alpha (GNAS1), is the G protein component of the olfactory signal transduction cascade. Mutations in the GNAS1 gene leading to Gs alpha protein deficiency are known to be associated with pseudohypoparathyroidism Ia (Albright hereditary osteodystrophy) and certain pituitary tumors with acromegaly. Studies on the human--mouse somatic cell hybrids provisionally assigned this gene to chromosome 20. We have now confirmed this localization on chromosome 20 and regionally assigned the GNAS1 gene to 20q12-q13.2 by in situ hybridization.

Chromosome Banding↗

PubMed1991

Differential effects of long-term lithium and carbamazepine administration on Gs alpha and Gi alpha protein in rat brain.

The G protein subunits, Gs alpha, Gi alpha, and Go alpha, have been quantitated in various rat brain regions using enzyme-linked immunosorbent assay (ELISA) techniques. Chronic (3-week) treatment with carbamazepine decreased Gs alpha in several brain regions reaching significance in the neostriatum, while chronic lithium treatment had no unequivocal effect. Lithium significantly increased Gi alpha in the hypothalamus and hippocampus, whereas carbamazepine decreased Gi alpha in the frontal cortex. Both treatments had no consistent effects on Go alpha. We conclude that long-term treatment with lithium and carbamazepine exerts differential effects on G protein alpha subunits, and that this modification of signal transduction represents a potential mechanism of antibipolar drug-induced neural plasticity.

Animals↗

PubMed2004

Effect of carbohydrates on fructosyltransferase expression and distribution in Streptococcus mutans GS-5 biofilms.

Streptococcus mutans produces a fructosyltransferase (FTF) enzyme, which synthesizes fructan polymers from sucrose. Fructans contribute to the virulence of the biofilm by acting as binding sites for S. mutans adhesion and as extracellular nutrition reservoir for the oral bacteria. Antibodies raised against a recombinant S. mutans FTF were used to test the effect of glucose, fructose, and sucrose on FTF expression in S. mutans GS-5 biofilms. Biofilms formed in the presence of fructose and glucose showed a higher ratio of FTF compared to biofilms formed in the presence of sucrose. Confocal laser scanning microscopy images of S. mutans biofilms indicated a carbohydrate-dependent FTF distribution. The layer adjacent to the surface and those at the liquid interface displayed high amounts cell-free FTF with limited amount of bacteria while the in-between layers demonstrated both cell-free FTF and cells expressing cell-surface FTF. Biofilm of S. mutans grown on hydroxyapatite surfaces expressed several FTF bands with molecular masses of 160, 125, 120, 100, and 50 kDa, as detected by using FTF specific antibodies. The results show that FTF expression and distribution in S. mutans GS-5 biofilms is carbohydrate regulated.

Antibodies, Bacterial↗

PubMed1993

Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein GS.

McCune-Albright syndrome (MCAS) is a sporadic disease classically including polyostotic fibrous dysplasia, café au lait spots, sexual precocity, and other hyperfunctional endocrinopathies. An activating missense mutation in the gene for the alpha subunit of GS, the G protein that stimulates cyclic adenosine monophosphate formation, has been reported to be present in these patients. The mutation is found in variable abundance in different affected endocrine and nonendocrine tissues, consistent with the mosaic distribution of abnormal cells generated by a somatic cell mutation early in embryogenesis. We describe three patients with MCAS who had profound endocrine and nonendocrine disease and who died in childhood. Two of the patients were severely ill neonates whose complex symptoms did not immediately suggest MCAS. A mutation of residue Arg201 of GS alpha was found in affected tissues from all three children. A review of the literature and unpublished case histories emphasizes the existence of other patients with severe and unusual clinical manifestations. We conclude that the manifestations of MCAS are more extensive than is generally appreciated, and may include hepatobiliary disease, cardiac disease, other nonendocrine abnormalities, and sudden or premature death.

Adolescent↗

PubMed1998

Adrenergic receptors in premenstrual dysphoric disorder. II. Neutrophil beta2-adrenergic receptors: Gs protein coupling, phase of menstrual cycle and prediction of luteal phase symptom severity.

Abnormal beta2-adrenergic receptor coupling to Gs protein is implicated in depressive disorders. Steroid hormones and antidepressants modulate beta-adrenergic receptor coupling, which may relate to the therapeutic efficacy of antidepressants. We examined beta2-adrenergic receptors in 18 patients with premenstrual dysphoric disorder (PMDD), in 15 control subjects during the follicular phase and in 12 patients during late luteal phase. Antagonist-measured receptor density, agonist-measured receptor density in the high- and low-conformational states and agonist affinity to both states were measured. Coupling indices to Gs protein were determined from agonist-displacement experiments. Follicular beta2-adrenergic receptor density was higher in patients than in control subjects, with a trend for higher receptor density in the high-conformational state. The phase of menstrual cycle had no effect on beta2-adrenergic receptor regulation in PMDD. Exploratory correlations showed that the K(L)/K(H) ratio was related to anxiety ratings in control subjects and %R(H) was correlated with symptom severity in patients. In patients, follicular beta2-adrenergic receptor binding measures were correlated with luteal symptom severity. These findings suggest abnormal beta2-adrenergic receptor regulation in PMDD. Further exploration of the role of beta-adrenergic receptor kinase, sex steroid hormones and antidepressants on beta-adrenergic receptor regulation in PMDD is warranted.

Adult↗

PubMed2002

Design, synthesis, and neuraminidase inhibitory activity of GS-4071 analogues that utilize a novel hydrophobic paradigm.

Structure-based design has led to the synthesis of a novel analogue of GS-4071, an influenza neuraminidase inhibitor, in which the basic amino group has been replaced by a hydrophobic vinyl group. An X-ray co-crystal structure of the new inhibitor (K(i)=45 nM) bound to the active site shows that the vinyl group occupies the same subsite as the amino group in GS-4071.

Acetamides↗