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Gradient-dependent ...
Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors
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- Macwan, Ankit (author)
- Linköpings universitet,Avdelningen för klinisk kemi,Medicinska fakulteten
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- Boknäs, Niklas (author)
- Linköpings universitet,Avdelningen för klinisk kemi,Medicinska fakulteten,Region Östergötland, Hematologiska kliniken US
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- Ntzouni, Maria (author)
- Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
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- Ramström, Sofia, 1973- (author)
- Linköpings universitet,Örebro universitet,Institutionen för medicinska vetenskaper,Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden,Avdelningen för klinisk kemi,Medicinska fakulteten,Region Östergötland, Klinisk kemi,Orebro Univ, Sweden
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- Gibbins, Jonathan M. (author)
- Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK,Univ Reading, England
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- Faxälv, Lars (author)
- Linköpings universitet,Avdelningen för klinisk kemi,Medicinska fakulteten,Region Östergötland, Klinisk kemi
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- Lindahl, Tomas (author)
- Linköpings universitet,Avdelningen för klinisk kemi,Medicinska fakulteten,Region Östergötland, Klinisk kemi
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(creator_code:org_t)
- 2019-01-10
- 2019
- English.
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In: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 104:7
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Abstract
Subject headings
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- As platelet activation is an irreversible and potentially harmful event, platelet stimulatory signaling must be tightly regulated to ensure the filtering-out of inconsequential fluctuations of agonist concentrations in the vascular milieu. Herein, we show that platelet activation via G protein-coupled receptors is gradient-dependent that is determined not only by agonist concentrations per se but also by how rapidly concentrations change over time. We demonstrate that gradient-dependent inhibition is a common feature of all major platelet stimulatory G protein-coupled receptors, while platelet activation via the non- G protein-coupled receptor glycoprotein VI is strictly concentration-dependent. By systematically characterizing the effects of variations in temporal agonist concentration gradients on different aspects of platelet activation, we demonstrate that gradient-dependent inhibition of protease-activated receptors exhibit different kinetics, with platelet activation occurring at lower agonist gradients for protease-activated receptor 4 than for protease-activated receptor 1, but share a characteristic bimodal effect distribution, as gradient-dependent inhibition increases over a narrow range of gradients, below which aggregation and granule secretion is effectively shut off. In contrast, the effects of gradient-dependent inhibition on platelet activation via adenosine diphosphate and thromboxane receptors increase incrementally over a large range of gradients. Further, depending on the affected activation pathway, gradient-dependent inhibition results in different degrees of refractoriness to subsequent autologous agonist stimulation. Mechanistically, our study identifies an important role for the cyclic adenosine monophosphate-dependent pathway in gradient-dependent inhibition. Together, our findings suggest that gradient-dependent inhibition may represent a new general mechanism for hemostatic regulation in platelets.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Keyword
- Arterial Thrombosis
- G protein coupled receptors
- Platelets
- Protease activated receptors
Publication and Content Type
- ref (subject category)
- art (subject category)
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