Membrane Surface Specialization of Blood Platelet and Megakaryocyte

Nakao, Komei; Angrist, Alfred

doi:10.1038/217960a0

Cited by 55 publications

(24 citation statements)

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“…1). This rapid uptake suggested that most of the drug binds directly to the plasma membrane of the platelet or to the layer of plasma protein surrounding this membrane (Nakao & Angrist, 1968;Behnke, 1968 Table 1). Maximal binding of quinidine was 53% when the total quinidine concentration was 10-lm.…”

Section: Resultsmentioning

confidence: 99%

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Accumulation of quinidine by human blood platelets: effects on platelet ultrastructure and 5‐hydroxytryptamine

Boullin

O'Brien

1971

British J Pharmacology

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Summary1. We have studied the mechanism of quinidine uptake by normal human blood platelets. 2. Platelets in plasma or Krebs solution took up quinidine extremely rapidly, the maximal drug concentration ratio of platelet to medium being 24 to 1 after 1 minute. 3. The effects of metabolic inhibitors on uptake were equivocal. Ouabain had no effect but iodoacetate and dinitrophenol were effective. However, as accumulation was not inhibited by low temperature, it was probably not energy dependent. 4. Interactions between quinidine and 5-HT were also investigated. 5. Quinidine blocked 5-HT uptake, but conversely, neither 5-HT itself nor 5-HT uptake inhibitors, such as cocaine, dexamphetamine, and desipramine interfered with quinidine accumulation. 6. Electronmicrographs of platelets incubated with 10-5, 10-4 or 2 x 10-3M quinidine in Krebs solution for 2 h showed no changes at the lower concentrations, but gross ultastructural damage, including disintegration of the plasma membrane, at 2 x 10-3M.7. Further evidence for intracellular penetration was obtained because quinidine released endogenous 5-HT and ATP, and also 14C-5-HT from loaded cells. 8. We conclude that quinidine is taken up by the platelet by a passive process, unrelated to the 5-HT transport mechanism. It is probably accumulated largely in the plasma membrane and outer protein layer, but intracellular penetration and ultrastructural damage may occur.9. Although the effects on 5-HT and ATP were not due to platelet damage, this may occur in vivo and be the cause of quinidine induced thrombocytopenic purpura.

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Section: Resultsmentioning

confidence: 99%

“…Plasma proteins form an outer layer on the platelet membrane (Nakao & Angrist, 1968;Behnke, 1968). These molecules might therefore bind considerable amounts of quinidine, and it has been suggested that quinidine acts on cells by virtue of avid binding to membrane proteins, thereby altering cell permeability (Conn & Luchi, 1961).…”

Section: Discussionmentioning

confidence: 99%

Accumulation of quinidine by human blood platelets: effects on platelet ultrastructure and 5‐hydroxytryptamine

Boullin

O'Brien

1971

British J Pharmacology

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“…In particular, there is the formation of an expansive and interconnected membranous network of cisternae and tubules, called the demarcation membrane system (DMS), which was originally thought to divide the megakaryocyte cytoplasm into small fields where individual platelets would assemble and subsequently release (13). DMS membranes have continuity with the plasma membrane (14,15) and are now thought to function primarily as a membrane reservoir for the formation of proplatelets, the precursors of platelets. A dense tubular network (16) and the open canalicular system, a channeled system for granule release, are also formed before the assembly of proplatelets begins.…”

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confidence: 99%

The biogenesis of platelets from megakaryocyte proplatelets

Patel¹

2005

Journal of Clinical Investigation

500

406

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Platelets are formed and released into the bloodstream by precursor cells called megakaryocytes that reside within the bone marrow. The production of platelets by megakaryocytes requires an intricate series of remodeling events that result in the release of thousands of platelets from a single megakaryocyte. Abnormalities in this process can result in clinically significant disorders. Thrombocytopenia (platelet counts less than 150,000/µl) can lead to inadequate clot formation and increased risk of bleeding, while thrombocythemia (platelet counts greater than 600,000/µl) can heighten the risk for thrombotic events, including stroke, peripheral ischemia, and myocardial infarction. This Review will describe the process of platelet assembly in detail and discuss several disorders that affect platelet production. Platelet formationMegakaryocyte development. Megakaryocytes are rare myeloid cells (constituting less than 1% of these cells) that reside primarily in the bone marrow (1) but are also found in the lung and peripheral blood. In early development, before the marrow cavities have enlarged sufficiently to support blood cell development, megakaryopoiesis occurs within the fetal liver and yolk sac. Megakaryocytes arise from pluripotent HSCs that develop into 2 types of precursors, burst-forming cells and colony-forming cells, both of which express the CD34 antigen (2). Development of both cell types continues along an increasingly restricted lineage culminating in the formation of megakaryocyte precursors that develop into megakaryocytes (1). Thrombopoietin (TPO), the primary regulator of thrombopoiesis, is currently the only known cytokine required for megakaryocytes to maintain a constant platelet mass (3). TPO is thought to act in conjunction with other factors, including IL-3, IL-6, and IL-11, although these cytokines are not essential for megakaryocyte maturation (4).Megakaryocytes tailor their cytoplasm and membrane systems for platelet biogenesis. Before a megakaryocyte has the capacity to release platelets, it enlarges considerably to an approximate diameter of 100 µm and fills with high concentrations of ribosomes that facilitate the production of platelet-specific proteins (5). Cellular enlargement is mediated by multiple rounds of endomitosis, a process that amplifies the DNA by as much as 64-fold (6-9). TPO, which binds to the c-Mpl receptor, promotes megakaryocyte endomitosis. During endomitosis, chromosomes replicate and the nuclear envelope breaks down. Although interconnected mitotic spindles assemble, the normal mitotic cycle is arrested during anaphase B. The spindles fail to separate, and both telophase and cytokinesis are bypassed. Nuclear envelope reformation (10, 11) results in a polyploid, multilobed nucleus with DNA contents ranging from 4N up to 128N within each megakaryocyte (12).In addition to expansion of DNA, megakaryocytes experience significant maturation as internal membrane systems, granules, and organelles are assembled in bulk during their development. In particular, there is th...

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“…The demarcation membrane system (DMS) is a complex network of membrane-bounded cisternae and tubules originally thought to subdivide the cytoplasm of the megakaryocyte into fields or territories from which platelets would release via fragmentation [32]. It has become clear, however, that the elaboration of highly elongated proplatelets requires a dramatic increase in the membrane surface area and that the DMS serves as this membrane reserve as first proposed by Radley in 1982 [32] (see also [33][34][35]). A recent study by Schulze et al [36 ] has directly visualized this DMS evagination process, and shown the DMS membrane to mature and fill with the polyphosphatydilinositol lipid, PI-4,5-P 2 , just before proplatelet formation.…”

Section: The Cytoplasmic Maturation Of Megakaryocytesmentioning

confidence: 97%