Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Nb2 node lymphoma cell line has been widely used as a model for investigating lactogen cellular actions. Both pertussis (PTX) and cholera (CTX) toxins modulate lactogen-stimulated Nb2 cell mitogenesis, suggesting G protein involvement in lactogen signal transduction. The following studies were performed to further investigate this possibility. Both PTX-sensitive (41 kDa) and CTX-sensitive substrates (42 and 45 kDa) were identified in Nb2 cell membrane and recognized by specific anti-Gi and anti-Gs antibodies, respectively. Equal numbers of Nb2 cells were then incubated with the lactogen human growth hormone (hGH, 10 ng/ml) for 0-72 h. Membrane protein prepared from each time point (50 micrograms) was compared in toxin-stimulated ADP-ribosylation studies. CTX-stimulated ADP-ribosylation was unaffected by prior hGH incubation. PTX-stimulated ADP-ribosylation increased 237 +/- 69% (X +/- S.E.) compared with 0-h controls (n = 11; p less than 0.01) after 4-7 h of hGH incubation then decreased toward 0-h samples by 24 and 72 h. No change in Gi alpha concentration was observed, but beta subunit concentration increased (145 +/- 14% at 7 h; p less than 0.01; n = 3) in a time course that paralleled the changes in PTX-stimulated ADP-ribosylation. In summary, 1) both Gi and Gs were present in Nb2 cell membrane, 2) incubation of cells with a lactogen, hGH, for 4-7 h markedly enhanced PTX-stimulated ADP-ribosylation of Gi alpha in vitro, whereas CTX-stimulated ADP-ribosylation of Gs alpha was unchanged, and 3) although no change in Gi alpha concentration was observed, beta subunit concentration increased in parallel with the increase in PTX-stimulated ADP-ribosylation of Gi alpha. These results suggest that hGH may modify PTX-stimulated ADP-ribosylation of Gi not by changing Gi alpha concentration, perhaps by increasing beta subunit concentration, enhancing association of Gi alpha by beta gamma subunits, which, in turn, is preferentially ADP-ribosylated. This may represent a late signal transduction event and may also have implications for other effectors dependent on Gi-mediated events.
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PMID:Human growth hormone enhances pertussis toxin-stimulated ADP-ribosylation of Gi in Nb2 cell membrane. 158 39

This laboratory has previously demonstrated that there is an opiate receptor-mediated, concentration-dependent modulation of the electrically stimulated release of enkephalin from the guinea pig myenteric plexus. Low doses of opioids (nanomolar) enhance release, whereas higher concentrations (10-100 nM) inhibit release. We now demonstrate that the in vivo i.p. administration of the islet-activating protein from pertussis toxin (PTX; 50 micrograms/500 g of body weight) markedly diminishes the potency of mu, delta, or kappa-selective opioids to inhibit the evoked release of enkephalin. In contrast, PTX is without effect on the enhancement of enkephalin release observed after treatment with nanomolar concentrations of the above opioids. Conversely, pretreatment with cholera toxin (CTX; 0.01 nM for 3 hr in vitro) has no effect on the mu, delta, or kappa opioid inhibition of evoked enkephalin release but abolishes the ability of nanomolar concentrations of these agonists to enhance stimulated enkephalin release. These data indicate that different classes of guanine nucleotide-binding proteins (G proteins) appear to mediate the opioid enhancement or inhibition of stimulated enkephalin release. Furthermore, they suggest that a PTX-sensitive G protein (Gi or Go) and a CTX-sensitive G protein (Gs) are integral components of the mechanism that mediates opioid inhibition and opioid enhancement, respectively, of evoked enkephalin release. To our knowledge, this report represents the first demonstration that Gs-coupled opiate receptors (in addition to those that are coupled to Gi) can modulate transmitter release.
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PMID:Different G proteins mediate the opioid inhibition or enhancement of evoked [5-methionine]enkephalin release. 182 85

G proteins are membrane-bound molecules involved in coupling of surface receptors with signal transduction effector systems in multiple cell types including T lymphocytes. Given that mature T cells which lack antigen receptors (CDl-Ti) are refractory to stimulation through CD2 or other accessory molecules, T cell receptor components likely play a critical role in coupling surface receptors with signal transduction effectors. It has recently been proposed that modulation of T cell receptor components with MAbs results in a physical loss or functional inactivation of G protein(s). In view of the importance of the T cell activation process, we herein examined G proteins in untreated or antibody-modulated Jurkat T cells as well as in genetic variants lacking either CD3-Ti or CD2 surface receptors. 43- and 41-kDa G protein alpha chains are ADP ribosylated with cholera (CTX) and pertussis (PTX) toxins, respectively, in wild type and receptor minus cell populations. In the wild type Jurkat cell line as well as in CD3- and CD2- variants, AlF4- can activate the G protein(s) presumably associated with phospholipase C to generate polyphosphoinositide turnover as well as an increase in cytoplasmic free calcium ions. Furthermore, G protein(s) linked to adenylylcyclase, a pathway which inhibits T lymphocyte activation, can be directly activated with CTX in the absence of CD3-Ti or CD2 on the membrane. Importantly, AlF4- can also induce polyphosphoinositide turnover in Jurkat cells whose T cell receptor proteins have been modulated with anti-CD3 MAb. These data provide functional and biochemical evidence that at least certain G proteins are intact in the absence of surface expression of CD3-Ti or CD2 molecules and imply that CD3-Ti desensitization is not singularly due to G protein loss.
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PMID:Characterization of functional GTP binding proteins in Jurkat T cell mutants lacking either CD3-Ti or CD2 surface receptors. 197 60

Binding of chemoattractants to specific cell surface receptors on polymorphonuclear leukocytes (PMNs) initiates a series of biochemical responses leading to cellular activation. A critical early biochemical event in chemoattractant (CTX) receptor-mediated signal transduction is the phosphodiesteric cleavage of plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2), with concomitant production of the calcium mobilizing inositol-1,4,5-trisphosphate (IP3) isomer, and the protein kinase C activator, 1,2-diacylglycerol (DAG). The following lines of experimental evidence collectively suggest that CTX receptors are coupled to phospholipase C via a guanine nucleotide binding (G) protein. Receptor-mediated hydrolysis of PIP2 in PMN plasma membrane preparations requires both fMet-Leu-Phe and GTP, and incubation of intact PMNs with pertussis toxin (which ADP ribosylates and inactivates some G proteins) eliminates the ability of fMet-Leu-Phe plus GTP to promote PIP2 breakdown in isolated plasma membranes. Studies with both PMN particulate fractions and with partially purified fMet-Leu-Phe receptor preparations indicate that guanine nucleotides regulate CTX receptor affinity. Finally, fMet-Leu-Phe stimulates high-affinity binding of GTP gamma S to PMN membranes as well as GTPase activity. A G alpha subunit has been identified in phagocyte membranes which is different from other G alpha subunits on the basis of molecular weight and differential sensitivity to ribosylation by bacterial toxins. Thus, a novel G protein may be involved in coupling CTX receptors to phospholipase C. Studies in intact and sonicated PMNs demonstrate that metabolism of 1,4,5-IP3 proceeds via two distinct pathways: 1) sequential dephosphorylation to 1,4-IP2, 4-IP1 and inositol, or 2) ATP-dependent conversion to inositol 1,3,4,5-tetrakisphosphate (IP4) followed by sequential dephosphorylation to 1,3,4-IP3, 3,4-IP2, 3-IP1 and inositol. Receptor-mediated hydrolysis of PIP2 occurs at ambient intracellular Ca2+ levels; but metabolism of 1,4,5-IP3 via the IP4 pathway requires elevated cytosolic Ca2+ levels associated with cellular activation. Thus, the two pathways for 1,4,5-IP3 metabolism may serve different metabolic functions. Additionally, inositol phosphate production appears to be controlled by protein kinase C, as phorbol myristate acetate (PMA) abrogates PIP2 hydrolysis by interfering with the ability of the activated G protein to stimulate phospholipase C. This implies a physiologic mechanism for terminating biologic responses via protein kinase C mediated feedback inhibition of PIP2 hydrolysis.
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PMID:Regulation of inositol phospholipid and inositol phosphate metabolism in chemoattractant-activated human polymorphonuclear leukocytes. 312 97

Rat brain cannabinoid receptor (CB-1) was stably transfected into the murine tumor line AtT-20 to study its coupling to inwardly rectifying potassium currents (Kir) and high voltage-activated calcium currents (ICa). In cells expressing CB-1 ("A-2" cells), cannabinoid agonist potently and stereospecifically activated Kir via a pertussis toxin-sensitive G protein. ICa in A-2 cells was sensitive to dihydropyridines and omega CTX MVIIC, less so to omega CgTX GVIA and insensitive to omega Aga IVa. In CB-1 expressing cells, cannabinoid agonist inhibited only the omega CTX MVIIC-sensitive component of ICa. Inhibition of Q-type ICa was voltage dependent and PTX sensitive, thus similar in character to the well-studied modulation of N-type ICa. An endogenous cannabinoid, anandamide, activated Kir and inhibited ICa as efficaciously as potent cannabinoid agonist. Immunocytochemical studies with antibodies specific for class A, B, C, D, and E voltage-dependent calcium channel alpha 1 subunits revealed that AtT-20 cells express each of these major classes of alpha 1 subunit.
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PMID:Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. 747 17

The nature of melatonin receptor-G-protein coupling in ovine pars tuberalis (PT) cells of the pituitary was addressed using cholera (CTX) and pertussis (PTX) toxins. ADP-ribosylation of ovine PT membrane proteins using 32P-NAD in the presence of CTX radiolabelled several substrates including 44, 51, and 60 kD proteins. Each were clearly distinct from the 40 kD substrate radiolabelled in the presence of PTX. Acute incubation of PT membranes with either toxin reduced the number of high affinity binding sites for 125I-MEL, although the magnitude of the inhibition was much greater for CTX (56%) than for PTX (20%). A CTX-sensitive component also mediates the inhibition of forskolin-stimulated cyclic AMP accumulation as pre-treatment of PT cells with CTX (5 micrograms/ml) for 16 h blocked this response. Gs alpha is a major substrate for ADP-ribosylation by CTX, and 16 h pre-treatment of PT cells with CTX (5 micrograms/ml) caused a down-regulation of Gs alpha. Northern analysis showed only one major transcript of Gs alpha of about 2 kb, which would encompass all of the known splice variants of the Gs gene. Screening of a cDNA library from ovine PT for Gs-related genes and sequencing of clones, combined with RT-PCR of PT mRNA, revealed no novel products. On this basis it is concluded that the CTX substrate is unlikely to be a novel splice variant or related gene product of the Gs class of G-protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Melatonin receptors couple through a cholera toxin-sensitive mechanism to inhibit cyclic AMP in the ovine pituitary. 755 Feb 82

We have examined the functional consequences of G protein coupling to calcium-activated potassium (KCa) channels using isometric tension records from guinea pig tracheal smooth muscle. After incubation with 1 microgram/ml pertussis toxin (PTX) for 6 h, the contraction response to 1 microM methacholine (MCh) was suppressed by 31.7 +/- 5.0% (n = 10). Similarly, the contraction was inhibited by 29.1 +/- 5.0% (n = 6) after application of 0.1 microM AF-DX 116, an M2-selective muscarinic receptor antagonist. Cholera toxin (CTX, 2.0 micrograms/ml for 6 h), which activates the stimulatory G protein of adenylyl cyclase (Gs), also suppressed contraction by 43.9 +/- 3.3% (n = 11). The inhibitory effects of PTX, AF-DX 116, or CTX were reversed in the presence of 100 nM charybdotoxin (ChTX), a selective KCa channel inhibitor. These findings suggest that disruption of inhibitory coupling between muscarinic receptor and KCa channels mediated by PTX-sensitive G proteins, or KCa channel activation induced by Gs/adenylyl cyclase-linked processes, antagonizes muscarinic contraction. The isoproterenol concentration-inhibition curves for precontracted trachea (1 microM MCh) were shifted to the left after perfusion with PTX or AF-DX 116, and the leftward shift of the curve was blocked by ChTX. Thus direct or indirect regulation of KCa channels mediated by the inhibitory guanine nucleotide binding protein (Gi) and Gs may play a functionally important role in the mechanical antagonism by the two receptor agonists.
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PMID:Role of G proteins and KCa channels in the muscarinic and beta-adrenergic regulation of airway smooth muscle. 786 43

After intravitreal injections of cholera or pertussis toxin (CTX or PTX, 0.5 -1 microgram/eye) into the albino rabbit eye, the in vitro responses of ciliary process adenylyl cyclase (AC) to isoproterenol, vasoactive intestinal peptide (VIP), and forskolin (FSK) were increased 21-40% for PTX, but for CTX-injected eyes AC responses to fluoroaluminate, VIP and FSK decreased 70-50%. The increased responses after PTX suggests that this toxin blocked an inhibitory Gi control of AC that is present in the control tissue. However, prolonged (> 24 hr) in vivo exposure to CTX appears to down-regulate the AC enzyme. In contrast to the in vivo findings, AC responsiveness was unaffected by PTX pre-treatment of membranes in vitro, while CTX pre-treatment increased basal activity (+600%), and the FSK response (+30%), but decreased responsiveness to fluoroaluminate, VIP and isoproterenol by 88-56%. Treatment of ciliary process membranes with 32P-NAD and CTX or PTX followed by SDS-PAGE autoradiography of labelled proteins gave two bands for the G-protein alpha-subunits of Gs (45, 56 kDa) and one broad band centered at 40 kDa for Gi-type subunits respectively. Western blots using specific antibodies showed the presence of Gi type I or III, but no detectable Gi type II or Go in rabbit ciliary processes. We conclude that the changes in adenylyl cyclase enzyme responses after intraocular CTX or PTX may not correlate with cAMP levels and intraocular pressure effects. However, the in vitro biochemical data on AC responses and on G-proteins provide evidence for dual regulation of ciliary process AC by activating and inhibitory G-proteins.
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PMID:Role of G-proteins in ciliary process adenylyl cyclase responses of the albino rabbit eye. 803 85

Intravitreal injections of cholera or pertussis toxin (CTX or PTX, 0.5-1 microgram/eye) decreased intraocular pressure (IOP) up to 50% in the albino rabbit eye, which lasted up to six days. Both toxins were active on G-proteins as determined by in vitro and in vivo effects on ciliary process adenylyl cyclase activity and by ADP ribosylation of G-protein alpha-subunits with 32P-NAD. However, forty-two hours after toxin injection aqueous humor proteins increased from control levels of 0.8-1.2 mg/ml to 8-25 mg/ml. Both toxins contained 1-3 parts per thousand endotoxin sufficient to cause the IOP and aqueous humor protein responses observed. We conclude that the in vivo responses to intraocular CTX or PTX obtained from commercial sources may not provide unequivocal evidence for the role(s) of G-proteins in aqueous humor dynamics, and must be interpreted with caution.
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PMID:Endotoxins in cholera and pertussis toxins interfere with in vivo responses to these agents in the albino rabbit eye. 803 92

Modulation of the neuronal omega-conotoxin GVIA-sensitive N-type voltage-dependent calcium channel (VDCC) by neurotransmitters and guanine nucleotides suggests a dynamic interaction between activated G-protein alpha subunits and the N-type VDCC. Our previous report on the purification of the N-type VDCC (McEnery, M. W., Snowman, A. M., Sharp, A. H., Adams, M. E., and Snyder, S. H. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 11095-11099), has led us to investigate a possible association of CTXR with an endogenous G alpha subunit. The addition of the G-protein activator AIF4- modulated the 125I-CTX binding characteristics of the solubilized CTXR. Further immunological analyses employing G alpha subunit-specific antibodies to monitor the cofractionation of G alpha with 125I-CTX binding activity throughout the purification procedure indicate the selective recovery of Go alpha in the purified CTXR preparation, as neither Gs alpha, Gi alpha, nor G beta gamma could be detected. Furthermore, Go alpha associated with CTXR acted as a substrate for pertussis toxin-dependent ADP-ribosylation only upon the addition of exogenous G beta gamma subunits. These results strongly indicate a high affinity complex between an activated Go alpha and CTXR maintained throughout biochemical purification of the 125I-CTX receptor.
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PMID:The association of endogenous Go alpha with the purified omega-conotoxin GVIA receptor. 827 42


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