Botulinum C2 toxin ADP-ribosylates actin and enhances O2- production and secretion but inhibits migration of activated human neutrophils.

Norgauer, Johannes; Kownatzki, E.; Seifert, Roland; Aktories, Klaus

doi:10.1172/jci113741

Cited by 79 publications

(40 citation statements)

References 27 publications

(22 reference statements)

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“…The rate and duration of the neutrophil respiratory burst, which is one of the responses activated by the FPR system (27), is enhanced by dihydrocytochalasin B (dhCB), an alkaloid that disrupts microfilaments (28). Similar results were obtained after botulinum C2 toxin treatment of neutrophils, which results in ADP-ribosylation of actin (29) and its subsequent depolymerization. At physiological temperatures FPR becomes transiently associated with the cytoskeleton.…”

Section: Fpr Signaling An9 the Cytoskeletonmentioning

confidence: 73%

Cytoskeletal regulation of chemotactic receptors: Molecular complexation of N‐formyl peptide receptors with G proteins and actin

Jesaitis

Klotz

1993

European J of Haematology

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Signal transduction via receptors for N-formylmethionyl peptide chemoattractants (FPR) on human neutrophils is a highly regulated process. It involves direct interaction of receptors with heterotrimeric G-proteins and may be under thc control of cytoskeletal clemcnts. Evidencc exists suggesting that thc cytoskeleton and/or the membrane ske1eton determines the distribution of FPR in the plane of the plasma membrane, thus controlling FPR accessibility to different protcins in functionally distinct membrane domains. In desensitized cells, FPR are restricted to domains which are depleted of G proteins but enriched in cytoskeletal proteins such as actin and fodrin. Thus, the G protein signal transduction partners of FPR become inacccssible to the agonist-occupied receptor, preventing cell activation. We are investigating the molecular basis for the interaction of FPR with the membrane skeleton, and our results suggest that FPR, and possibly other receptors, may directly bind to cytoskeletal proteins such as actin.Key words: chemotaxis -formyl peptidesreceptors -actin G proteins -cytoskeleton -membrane skeleton lntroduction Human neutrophils exploit the function of several receptor types to sense concentration gradients of chemoattractants, such as N-formylmethionyl peptides, complement fragment 5a (C5a), LTB 4 , or platelet-activating factor (1). N-formylmethionyl peptide chemoattractant receptors (FPR) are among the most thoroughly studied members of the family of receptors coupled to guanyl nucleotide-binding proteins (G protein). Agonist binding to FPR and other chemoattractant receptors results in a variety of host defensive responses of neutrophils including chemotaxis, adhesion, superoxide production, and secretion of hydrolytic enzymes and microbicidal factors (2, 3).The gene for FPR has recently been cloned (4) and sequenced. lts predicted amino acid sequence suggests that this receptor has seven transmembrane segments analogaus to other receptors coupled to heterotrimeric G-proteins (5). Signal transduction by such receptors is highly regulated, allowing cellular adaptation of a variety of responses to a wide 288 range of conditions. Desensitization is one such adaptive process that results in a blunted response in spite of the presence of agonist-occupied receptors. The mechanisms proposed to explain desensitization include receptor phosphorylation, Sequestration, and down regulation ( 6, 7). The regulation of the Ievel of G protein a subunits has also been implicated in desensitization (8). Wehave proposed a novel mechanism for desensitization of FPR in neutrophils which involves the submembranaus cytoskeleton or membrane skeleton (MSK) of the neutrophil. The principle of this mechanism is that the physical segregation of different components of the signal transduction system into different plasma membrane domains controls their accessibility, and hence, interaction. This article summarizes our current understanding of this process. Cytoskeleton and signal transductionAbundant evidence exists sug...

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Section: Fpr Signaling An9 the Cytoskeletonmentioning

confidence: 73%

Cytoskeletal regulation of chemotactic receptors: Molecular complexation of N‐formyl peptide receptors with G proteins and actin

Jesaitis

Klotz

1993

European J of Haematology

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“…It is suggested that NO production is responsible for the observed increases in cyclic GMP, and inhibitors of NO production such as L-NMMA inhibit chemotaxis. In addition, chemotaxis and superoxide anion generation can be dissociated by use of botulinum C2 toxin (Norgauer et al, 1988) which enhances O2-release but inhibits neutrophil migration. The mechanism by which PGE2 inhibits chemotaxis is under investigation.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the inhibitory effects of PGE₂ and selective EP agonists on chemotaxis of human neutrophils

Armstrong

1995

British J Pharmacology

103

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1 The aims of this study were to investigate the inhibitory effects of prostaglandin E2 (PGE2) on chemotaxis of N-formyl-methionyl-leucine-phenylalaiine (FMLP)-stimulated human neutrophils, and to test the hypothesis that cyclic AMP is the second messenger involved. For this purpose, the inhibitory effect of selective EP agonists, and the modulatory effects of the adenylate cyclase inhibitor, SQ 22536, the protein kinase A (PKA) inhibitors H-89 and Rp-cAMPS, and the type IV phosphodiesterase (PDE) inhibitors, rolipram and Ro20-1724 have been examined. 2 Chemotaxis has been measured using blindwell chambers. When human neutrophils were stimulated with FMLP (100 nM), PGE2 inhibited chemotaxis in a concentration-dependent manner (0.01-10 Mm), with an EC50 of 90+24.5 nm, a maximum effect ranging from 45-75% and a mean inhibition of 64.5 ± 2.4%.

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“…Superoxide anion production was analyzed as superoxide-dismutase-iiihibitable reduction of cytochrome c at 550 nm as described [23].…”

Section: Methodsmentioning

confidence: 99%

Chemotactic 5‐Oxo‐Icosatetraenoic Acids Activate A Unique Pattern of Neutrophil Responses

Norgauer

Barbisch

Czech

et al. 1996

European Journal of Biochemistry

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Neutrophil cell responses and signal pathways elicted by the chemotactic arachidonic acid metabolites (6E, SZ, 1 lZ, 14Z)-5-oxo-icosatetraenoic acid and (6E, SZ, 1 IZ, 13E)-5-oxo-15-hydroxy-icosatetraenoic acid were studied and compared with those of other chemotaxins. Polyphosphoinositol lipid analysis revealed activation of phosphatidylinositol-bisphosphate 3-kinase by both agonists. Experiments with Fura-2 in the presence of EGTA indicated Ca2+ mobilization from intracellular stores by both 5-OXOicosanoids. A transient actin response and production of small amounts of superoxide anions upon stimulation with both agents was detected. The changes induced by 5-0x0-icosanoids were more moderate and transient than those obtained by other chemotaxins. Desensitization studies indicated cross-desensitization between both 5-oxo-icosanoids, but no interference with the response of other chemotaxins. All cell responses elicted by 5-0x0-icosanoids were inhibited by pertussis toxin suggesting involvement of Gproteins, a common activation mechanism for all known potent chemotaxins. In contrast to other chemotaxins, 5-0x0-icosanoids at concentrations 500-fold higher than the ED,, of other functions did not induce up-regulation of CD11 b and N-formyl-peptide receptors at the cell surface, and failed to potentiate Nformyl-peptide-induced superoxide anion production. These results indicate that 5-0x0-icosanoids trigger a unique pattern of neutrophil responses.Keywords: neutrophils ; 5-0x0-icosanoids ; Caz+ transients ; F actin; superoxide anions.Accumulation of neutrophils in tissue is characteristic of inflammation and observed in a large variety of pathological conditions. Leukocyte infiltration is presumably caused by different chemotaxins, which are generated by different mechanisms [I]. Extensively characterized chemotaxins are N-formyl peptides, the complement split product C5a (C5a), the chemokines interleukin-8 (IL-8) and GROa as well as the arachidonic acid metabolite leukotriene B, (LTB,) 11-61. In addition to chemotaxis, these substances stimulate with different capacity proinflammatory activities such as production of reactive oxygen metabolites, up-regulation of membrane proteins such as the complement receptor type 3 (CDllb) or the N-formyl-peptide receptor and priming of neutrophil responses [l -61. Activation of neutrophils by chemotaxins requires binding to ligand-specific cell-surface receptors [7]. The receptors for most chemotaxins interact with pertussis-toxin-sensitive or cholera-toxin-sensitive heterotrimeric guanine-nucleotide-binding proteins (G-proteins) 11, 7-91. Activation of G-proteins leads into different signal pathways initiated by phospholipase C-p2, phosphatidylinositol-bisphosphate (PtdInsP,) 3-kinase and actin polymerization [I, 2, 10, 1 I]. The second messengers generated by these differend signal pathways regulate the effector functions of leukocytes in concert [I, 2, 12-15].Recently, 5-oxo-icosanoids, i.e. (6E, SZ, 1 lZ, ~~Z ) -~-O X Oicosatetraenoic acid (5oETE) and (6E, 82, l l Z , 13E...

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Botulinum C2 toxin ADP-ribosylates actin and enhances O2- production and secretion but inhibits migration of activated human neutrophils.

Cited by 79 publications

References 27 publications

Cytoskeletal regulation of chemotactic receptors: Molecular complexation of N‐formyl peptide receptors with G proteins and actin

Cytoskeletal regulation of chemotactic receptors: Molecular complexation of N‐formyl peptide receptors with G proteins and actin

Investigation of the inhibitory effects of PGE₂ and selective EP agonists on chemotaxis of human neutrophils

Chemotactic 5‐Oxo‐Icosatetraenoic Acids Activate A Unique Pattern of Neutrophil Responses

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Botulinum C2 toxin ADP-ribosylates actin and enhances O2- production and secretion but inhibits migration of activated human neutrophils.

Cited by 79 publications

References 27 publications

Cytoskeletal regulation of chemotactic receptors: Molecular complexation of N‐formyl peptide receptors with G proteins and actin

Cytoskeletal regulation of chemotactic receptors: Molecular complexation of N‐formyl peptide receptors with G proteins and actin

Investigation of the inhibitory effects of PGE2 and selective EP agonists on chemotaxis of human neutrophils

Chemotactic 5‐Oxo‐Icosatetraenoic Acids Activate A Unique Pattern of Neutrophil Responses

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Investigation of the inhibitory effects of PGE₂ and selective EP agonists on chemotaxis of human neutrophils