Receptor-independent activation of mast cells by bradykinin and related peptides.
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Bradykinin↗
Biomedical subjects
M Mousli
Publications and source records attributed to M Mousli.
A mechanism of action for anaphylatoxin C3a stimulation of mast cells.
Incubation of either C3a, C3ades Arg, or synthetic analogues of the C-terminal sequence of C3a with purified rat peritoneal mast cells resulted in a rapid and dose-dependent histamine release. The natural factors C3a and C3ades Arg were the most active of the factors tested exhibiting EC50 values of 3.3 and 2.2 microM, respectively. The corresponding 21- and 22-residue C-terminal analogues of C3a (Y21R and Y21) were less potent than intact factor exhibiting EC50 values of 10.9 and 25.1 microM, respectively. Histamine was released in a nonlytic manner and the mast cell stimulation by both natural and synthetic factors was sensitive to pertussis toxin, neuraminidase, benzalkonium chloride, and to an excess of calcium. C3a stimulated the generation of inositol polyphosphates that was inhibited by either pertussis toxin or benzalkonium chloride. The C3a anaphylatoxin also directly stimulates purified G proteins (i.e., GTPase activity) in a dose-dependent manner. The evident correlation between efficiency of C3a and C3a analogues to stimulate purified G proteins and their capacity to induce cellular histamine release led us to conclude that C3a fails to activate mast cells via a mechanism involving specific receptors on the cell. Instead, we propose that C3a either causes direct activation of G proteins of the Gi subtype, with a subsequent activation of phospholipase C, or interacts with a binding site of the cell surface specific for cationic molecules that is coupled to the G protein cascade.
Amino Acid Sequence↗
Natural polyamines stimulate G-proteins.
The natural polyamines spermine and spermidine, the biosynthetic precursor putrescine and their analogues cadaverine and tyramine stimulate the GTPase activity of purified GTP-binding proteins (Go/Gi) from calf brain reconstituted into phospholipid vesicles. The order of potency was spermine greater than spermidine greater than putrescine = cadaverine greater than tyramine. The physiological relevance of this observation was assessed, showing the same order of potency of polyamines in the stimulation of peritoneal and tracheal rat mast cells. The activation of rat mast cells by polyamines was inhibited by benzalkonium chloride or by a 2 h pretreatment of the cells with pertussis toxin. The increase in inositol phosphates evoked by polyamines was also inhibited by pertussis toxin. Therefore we propose that intracellular polyamines might control the basal level of second messengers and modulate extracellular signals transduced through G-protein-coupled receptors.
Animals↗
Insulin releasing effects of mastoparan and amphiphilic substance P receptor antagonists on RINm5F insulinoma cells.
It has been proposed that mastoparan (INLKALAALAKKIL) and other mast cell secretagogues such as substance P (SP) or compound 48/80 act by direct activation of the pertussis toxin (PTX)-sensitive G-proteins in intact cells. Here we have investigated whether or not the antagonists of SP, [D-Trp7,9,10] SP1-11 and [D-Trp7,9,10, N-leu11]SP1-11, can similarly induce exocytosis from RINm5F cells. In intact cells mastoparan and the SP antagonists stimulated insulin release in a dose-dependent manner at concentrations ranging from 10 to 100 microM. The maximal effect on insulin release, of both mastoparan and the SP antagonists was comparable to that obtained with 100 microM forskolin. Pretreatment of the intact cells, for 18 h with PTX or 6 h with cholera toxin, did not change the responses induced by both mastoparan and the SP antagonists. This absence of PTX effect, despite the fact that the three PTX substrates at 41, 40 and 39 kDa were ADP ribosylated after pretreatment suggests intrinsic differences between mast and RINm5F cells. Thus the SP antagonists behave similarly to mastoparan in its ability to induce insulin release in RINm5F cells. However, the higher concentrations required with RINm5F cells compared to that needed for mast cells suggest differences either in G-proteins composition or in the phospholipid composition of the membranes.
Adenosine Diphosphate Ribose↗
Evidence for the interaction of mast cell-degranulating peptide with pertussis toxin-sensitive G proteins in mast cells.
K(+)-channel blocker properties have been reported for mast cell-degranulating peptide (MCD) in the central nervous system, but its action mechanism in mast cells remains unknown. We studied the effect of MCD on the membrane potential of rat peritoneal mast cells using the fluorescent probe bis-oxonol. Unexpectedly, MCD induced a decrease in bis-oxonol fluorescence, in a rapid and then a slower phase, suggesting hyperpolarization of mast cells. Other K(+)-channel blockers, tetraethylammonium and 4-aminopyridine, did not significantly modify the bis-oxonol fluorescence and did not alter the effect of MCD. The late phase of bis-oxonol fluorescence decrease was inhibited by ouabain and by potassium deprivation, whereas histamine release was not affected. The first phase of putative hyperpolarization induced by MCD coincided with histamine release and with the generation of inositol polyphosphates. Prior treatment of the cells with pertussis toxin inhibited these effects of MCD. MCD stimulated the GTPase activity of purified G proteins (G0/Gi) in a concentration-dependent manner. These results indicate that the effect of MCD on mast cells is unrelated to K+ channels but that it is relevant to the activation of pertussis toxin-sensitive G proteins leading to the activation of phospholipase C. A direct interaction of MCD with G proteins is proposed, which, unlike mastoparan, does not require positive cooperativity.
Amino Acid Sequence↗
G-proteins as targets for non-immunological histamine releasers.
The molecular mechanism of action of several non-immunological histamine releasers has been investigated using pertussis toxin which interfers, via ADP-ribosylation, with some G-proteins. Pertussis toxin (100 ng/ml) inhibited histamine release induced by compound 48/80, substance P, mastoparan, peptide 401, bradykinin and spermine showing that a G-protein sensitive to pertussis toxin was involved in the non-immunological histamine release. All these compounds directly activate purified G-proteins. The sensitivity to pertussis toxin of this direct stimulatory effect was demonstrated for compound 48/80, mastoparan and substance P. Altogether these results suggest that a direct activation of G-protein might be the molecular mechanism of action of histamine secretagogues acting through a pertussis toxin sensitive G-protein and in this way mimic agonist-ligand receptor interaction.
Animals↗
Molecular basis for cellular effects of naturally occurring polyamines.
The naturally occurring polyamines, putrescine, spermidine and spermine, and the analogue cadaverine, induce a dose-dependent histamine release from rat peritoneal mast cells. Spermine was the most active among these polycationic metabolites, followed by spermidine and putrescine. The histamine release was inhibited by a 2 h pretreatment of the cells with pertussis toxin (100 ng/ml), demonstrating the involvement of a pertussis toxin-sensitive GTP-binding regulatory protein during the exocytotic process. Experiments performed with purified Go/Gi proteins reconstituted into phospholipid vesicles showed a direct stimulation of GTPase activity by the polyamines. This direct stimulation of G proteins and the consequent activation of the coupled effectors may represent a new mechanism of action for natural polyamines controlling receptor-dependent processes.
Animals↗
Direct activation of GTP-binding regulatory proteins (G-proteins) by substance P and compound 48/80.
The neuropeptide substance P and the polyamine compound 48/80, both known to activate mast cell secretory processes, increased the rate of GTP S binding to G-proteins purified from calf brain (Go/Gi mixture). The GTPase activity of G-proteins was also increased by substance P and compound 48/80 in a dose-dependent and Mg2+-dependent way. These effects were similar to those of the wasp venom peptide mastoparan, another histamine releaser of rat peritoneal and human skin mast cells. This suggests that the secretory property of compound 48/80 and substance P is not due to a receptor-mediated process but, like mastoparan, results from a direct activation of G-proteins.
Animals↗
A pertussis toxin-sensitive G protein is required to induce histamine release from rat peritoneal mast cells by bradykinin.
Bradykinin, kallidin (Lys-bradykinin) and [Thi 5,8, D-Phe7]-bradykinin, a functional B2 antagonist, induce histamine release from rat peritoneal mast cells. The histamine release is dependent upon added calcium when mast cells are placed in calcium-free medium 30 min before being triggered with the kinins. Histamine release was dose-dependently inhibited by pertussis toxin (1-100 ng/ml) and by benzalkonium chloride (0.1-3 micrograms/ml). The efficiency of ionophore A23187 on histamine release was affected neither by pertussis toxin nor by benzalkonium chloride. The parallel response of rat peritoneal mast cells to kinins and to substance P suggest that these peptides have the same mechanisms of action i.e. activation of a pertussis toxin-sensitive G protein and of phospholipase C defining a peptidergic triggering pathway of mast cells.
Animals↗
The sensitivity to Zn2+ discriminates between typical and atypical mast cells.
The effects of zinc gluconate have been studied on rat peritoneal mast cells and rat basophilic leukemia cells (RBL 2H3) stimulated by various secretagogues. The IC50's of zinc gluconate on peritoneal cells were (microM): 1.6, 1.9, 5.4 and 18 for ionophore A23187, phorbol 12-myristate 13-acetate, substance P and immunoglobulin E-antigen, respectively. Higher concentrations of zinc gluconate were required to inhibit histamine secretion from RBL 2H3 cells, i.e. 12 microM (ionophore A23187) and 140 microM (immunoglobulin E-antigen). Zinc gluconate (10(-4) to 10(-3) M) also inhibited the IgE-dependent contraction of guinea pig trachea but was unable to affect that induced by exogenous histamine. These results suggest that zinc gluconate acts intracellularly and is selective of "typical" or "connective tissue" mast cells.
Animals↗
Interaction of substance P, compound 48/80 and mastoparan with the alpha-subunit C-terminus of G protein.
Pretreatment of purified calf brain G proteins with activated pertussis toxin or antibodies raised against the C-terminus of their alpha subunits prevented the increase in GTPase activity induced by substance P, compound 48/80 and mastoparan. These results suggest that these mast cell secretagogues activate G proteins directly via an interaction with the C-terminus of alpha subunits of G proteins by mimicking the agonist-liganded receptors.
Amino Acid Sequence↗
G protein activation: a receptor-independent mode of action for cationic amphiphilic neuropeptides and venom peptides.
The neuropeptide substance P, the venom peptide mastoparan and the synthetic polyamine compound 48/80 activate rat peritoneal mast cells, leading to rapid histamine release by exocytosis. Although these effects are inhibited by pertussis toxin and involve a transient increase in IP3, no selective membrane receptors have been identified. However, it has recently been shown that these compounds activate G proteins in vitro. Here Yves Landry and colleagues discuss the proposal that direct activation of G protein is the physiological mechanism of action of substance P on rat peritoneal mast cells, this mechanism being mimicked by mastoparan and 48/80, and possibly by other cationic amphiphilic peptides such as kinins. These compounds might be of help in defining the interaction between membrane receptors and G proteins.
Amino Acid Sequence↗
[Neuropeptides and inflammation: presumed mechanisms in neurogenic inflammation].
Neuropeptides, among which substance P, VIP (Vasoactive intestinal peptide), somatostatin, neurotensin, dynorphin and enkephalins, are able to modulate inflammatory processes. Increasing interest is now devoted to these peptides in different inflammatory diseases, concerning skin, lung and joins. The effect of substance P can be dependent on its C-terminal moiety implicating by this way an interaction with specific neurokinin receptors or can be dependent on its N-terminal moiety which does not involve a specific membrane receptor. Such diversity of the action mechanisms of peptides should influence the evolution of the anti-inflammatory therapeutic.
Arthritis↗
Activation of Gi-like proteins, a receptor-independent effect of kinins in mast cells.
The peptide hormones bradykinin and kallidin (Lys-bradykinin), as well as their analogues [des-Arg9]-bradykinin, a selective B1 agonist, [des-Arg9,Leu8]-bradykinin, a selective B1 antagonist, and [Thi5,8,D-Phe7]-bradykinin and D-Arg0-[Hyp3,D-Phe7]-bradykinin, two selective B2 antagonists, induced rapid histamine release from purified rat peritoneal mast cells. In contrast, the N-terminal fragment bradykinin-(1-5) was inactive. These peptides also activate the GTPase activity of GTP-binding proteins (G proteins) (Go/Gi) purified from calf brain, with an order of potency identical to that observed on mast cells, [Thi5,8,D-Phe7]-bradykinin much greater than kallidin greater than bradykinin greater than D-Arg0-[Hyp3,D-Phe7]-bradykinin greater than [des-Arg9]-bradykinin greater than [des-Arg9,Leu8]-bradykinin greater than bradykinin-(1-5). This correlation suggested that G proteins are the targets of kinins in mast cells. Accordingly, the concomitant increase in inositol trisphosphates and release of histamine elicited by kinins were inhibited by pertussis toxin pretreatment of mast cells. The inhibitory effect of benzalkonium chloride showed that the G proteins involved belong to the Gi type. GTPase activity was measured in the supernatant of homogenized mast cells but not in the membranous fraction. This activity was stimulated by kinins and by the venom peptide mastoparan. The potency of peptides was similar to that observed with purified bovine G proteins. Sodium dodecyl sulfate-gel electrophoresis of mast cell supernatant revealed pertussis toxin-induced ADP-ribosylation of two proteins, in the Mr 41,000 and 40,000 range, i.e., similar to purified alpha-subunits of Gi1 and Gi2 or Gi3 subtypes. The data support the proposal that bradykinin and analogues act like mastoparan, substance P, and compound 48/80, interacting first with sialic acid residues of the cell surface and then with Gi-like proteins, inducing phospholipase C activation and intracellular calcium mobilization.
Adenosine Diphosphate Ribose↗
Resting plasma membrane potential of rat peritoneal mast cells is set predominantly by the sodium pump.
Changes in the plasma membrane potential of two histamine-releasing cells, rat peritoneal mast cells and basophilic leukemia cells 2H3 (RBL 2H3), were recorded with the potential-sensitive dye bis-oxonol. For mast cells, the presence of ouabain or the absence of K+ increased the fluorescence intensity of bis-oxonol; gramicidin had no effect. For RBL 2H3 cells, the presence of ouabain and the absence of K+ also increased bis-oxonol fluorescence but gramicidin also increased it. These results show that the plasma membrane potential of RBL 2H3 cells is set, in part, by the activity of the Na+ pump and in part by the K+ conductance, while that of rat mast cells is set predominantly by the Na+ pump.
Animals↗
Activation of rat peritoneal mast cells by substance P and mastoparan.
Incubation of rat peritoneal mast cells with substance P resulted in the transient stimulation of phosphoinositol breakdown and histamine secretion through an exocytotic process. These effects were inhibited markedly by a prior 2-hr exposure of the cells to pertussis toxin. Pertussis toxin also inhibited exocytosis induced by substance P, mastoparan and compound 48/80, but did not modify the secretory effect of the ionophore A23187. The transfer of rat peritoneal mast cells from balanced salt solution to calcium-free buffer led to a similar time-dependent decrease in their response to substance P and mastoparan. The concomitant absence of potassium from the calcium-free buffer enabled the mast cells to retain their secretory response. These data demonstrate identical dependency for calcium and monovalent ions of the secretory process elicited by substance P, mastoparan and compound 48/80. Pretreatment of mast cells with neuraminidase decreased the secretagogic effect of substance P, mastoparan and compound 48/80 without modifying the efficiency of the ionophore A23187. Thus, sialic acid residues might be involved in the initial binding of peptides and compound 48/80 to mast cells, which activate a pertussis toxin-sensitive G-protein and allows the increase in phospholipase C activity to induce exocytosis. This sequence of events might characterize the physiological pathway of mast cell activation by peptides, without necessarily requiring selective membrane receptors.
Animals↗
[Bronchial peptidergic control and concepts of neurogenic inflammation].
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Asthma↗
Peptidergic pathway in human skin and rat peritoneal mast cell activation.
The common pathway of heterogenous mast cell activation as mediated by antigens is through the cross-linking of IgE bound to Fc epsilon RI receptors. The peptidergic pathway of mast cell activation, achieved by cationic secretagogues, is restricted to "serosal" mast cells, the experimental models being rat peritoneal and human skin mast cells. Cationic secretagogues include positively charged peptides but also various amines such as compound 48/80 and natural polyamines. An early intracellular event of this pathway is the activation of pertussis toxin-sensitive G proteins. The correlation observed between the ability of basic compounds to trigger mast cell exocytosis and their potency to activate purified G proteins strongly suggests that cationic compounds activate mast cell G proteins via a receptor-independent but membrane-assisted process. In this paper, alternative mechanisms are discussed. The consequence of G protein stimulation is the activation of phospholipase C with an increase in inositol triphosphates. Natural polyamines are relatively poor triggers of mast cells (10(-4) to 10(-2) M). Neuropeptides such as substance P, neuropeptide Y or vasoactive intestinal peptide, peptidic hormones such as kinins, and venoms such as mastoparan and mast cell degranulating peptide, are all active in a concentration range from 10(-7) to 10(-4) M. The cationic anaphylatoxin C3a also stimulates mast cells at concentrations below precursor complement C3 blood levels. The component C3 of the complement system is one of only a few plasma proteins having activation fragments (i.e. C3a) that can be generated at micromolar levels. The effects of basic secretagogues defines a peptidergic pathway of mast cell activation, which represents a potentially toxic process considering the tissue effects caused by exogenous basic compounds such as venom peptides and certain amine containing drugs. Peptidergic activation of mast cells may also be a pathophysiological process having an important role in neurogenic inflammation and in diseases involving extensive activation of the blood complement cascade.
Amino Acid Sequence↗