Inhibitors of Na+/H+ exchange block stimulus-provoked arachidonic acid release in human platelets. Selective effects on platelet activation by epinephrine, ADP, and lower concentrations of thrombin.

Sweatt, J. David; Johnson, Sven-Rune; Cragoe, E. J.; Limbird, Lee E.

doi:10.1016/s0021-9258(17)38812-9

Cited by 137 publications

(2 citation statements)

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“…The interactions of GP Ilb-IBa with adhesion molecules are also important for activation of intracellular pathways that regulate several processes, including the activation of the Na+/H § antiporter and the Ca2+-dependent protease, calpain (2,12). In platelets treated with weak agonists, such as ADP, aggregation mediated by fibrinogen binding to GP llb-lIIa is also required for the stimulation of arachidonate metabolism and dense granule secretion (2,18,29,30).…”

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confidence: 99%

Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets.

Lipfert

Haimovich

Schaller

et al. 1992

The Journal of Cell Biology

655

454

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Abstract. We have investigated mechanisms involved in integrin-mediated signal transduction in platelets by examining integrin-dependent phosphorylation and activation of a newly identified protein tyrosine kinase, pp125 F~ (FAK, focal adhesion kinase). This kinase was previously shown to be localized in focal adhesions in fibroblasts, and to be phosphorylated on tyrosine in normal and Src-transformed fibroblasts. We show that thrombin and collagen activation of platelets causes an induction of tyrosine phosphorylation of pp125 F~ and that pp125 F~ molecules isolated from activated platelets display enhanced levels of phosphorylation in immune-complex kinase assays, pp125 F~ was not phosphorylated on tyrosine after thrombin or collagen treatment of Glanzmann's thrombasthenic platelets deficient in the fibrinogen receptor GPIIbIIIa, or of platelets pretreated with an inhibitory monoclonal antibody to GP lib-Ilia. Fibrinogen binding to GP Ub-HIa was not sufficient to induce pp125 F~x phosphorylation because pp125 F~ was not phosphorylated on tyrosine in thrombin-treated platelets that were not allowed to aggregate. These results indicate that tyrosine phosphorylation of pp125 s~ is dependent on platelet aggregation mediated by fibrinogen binding to the integrin receptor GP lib-Ilia. The induction of tyrosine phosphorylation of pp125 F~ was inhibited in thrombin-and collagen-treated platelets preincubated with cytochalasin D, which prevents actin polymerization following activation. Under all of these conditions, there was a strong correlation between the induction of tyrosine phosphorylation of pp125 r~ in vivo and stimulation of the phosphorylation of pp125 FA~ in vitro in immune-complex kinase assays. This study provides the first genetic evidence that tyrosine phosphorylation of pp125 F~ is dependent on integrin-mediated events, and demonstrates that there is a strong correlation between tyrosine phosphorylation of pp125 FAK in platelets, and the activation of pp125FAK-associated phosphorylating activity in vitro.T HE interactions of cells with extracellular adhesion molecules play critical roles in regulating the morphology, proliferation, migration, and differentiation of cells. One family of receptors for extracellular adhesion molecules, called integrins, is comprised of heterodimeric r transmembrane proteins (1,17,19,20). Although the extracellular interactions between adhesion molecules and their integrin receptors have been well characterized, the interactions of integrins with cytoplasmic targets and their role in signaling pathways that are responsible for adhesion-induced changes in cell behavior are poorly understood (5).Platelets provide a very useful model system for investigating the mechanisms involved in integrin-induced events. The best characterized platelet integrin receptor, GP Hb-HIa, is required for two essential functions of platelets in hemostasis-platelet-to-platelet aggregation and the spreading of J. S. Brugge's present address is Ariad Pharmaceuticals, Inc.,

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confidence: 99%

Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets.

Lipfert

Haimovich

Schaller

et al. 1992

The Journal of Cell Biology

655

454

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“…In parallel studies, we had shown that removal of extracellular Na + from platelet preparations eliminated α 2 -receptor-mediated platelet aggregation and secretion due to eliminating receptor activation of novel phospholipase A 2 -dependent priming of signaling for weak platelet agonists (30)(31)(32)(33)(34)(35)(36)(37). However, we later had to retract the findings because an enthusiastic graduate student had misled us to conclude that the α 2A -adrenergic receptor activated a Na + /H + exchanger (38,39) (see the sidebar titled Lessons Learned).…”

Section: A Transition To the Role Of Na + In Regulating Gpcrsmentioning

confidence: 99%

Pushing Forward the Future Tense: Perspectives of a Scientist

Limbird

2022

Annu. Rev. Pharmacol. Toxicol.

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This review is a somewhat chronological tale of my scientific life, emphasizing the why of the questions we asked in the lab and lessons learned that may be of value to nascent scientists. The reader will come to realize that the flow of my life has been driven by a combined life of the mind and life of the soul, intertwining like the strands of DNA. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Inhibition of Allergic Contact Dermatitis and Ultraviolet Radiation-Induced Tissue Swelling in the Mouse by Topical Amiloride

Gallo¹

1989

Arch Dermatol

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Amiloride is known to inhibit membrane sodium transport and has been shown in vitro to inhibit cell activation and proliferation in several model systems. These effects occur at relatively high local concentrations of amiloride. We studied the cutaneous response to the topical application of amiloride hydrochloride. Our observations demonstrated that topical application of amiloride was potent in its ability to inhibit murine tissue swelling and inflammation in response to contact sensitizing agents and ultraviolet radiation. These observations might suggest a role for amiloride or its analogues as topical anti-inflammatory or antiproliferative drugs.

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Inhibitors of Na+/H+ exchange block stimulus-provoked arachidonic acid release in human platelets. Selective effects on platelet activation by epinephrine, ADP, and lower concentrations of thrombin.

Cited by 137 publications

References 30 publications

Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets.

Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets.

Pushing Forward the Future Tense: Perspectives of a Scientist

Inhibition of Allergic Contact Dermatitis and Ultraviolet Radiation-Induced Tissue Swelling in the Mouse by Topical Amiloride

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