Platelets store signaling molecules (eg, serotonin and ADP) within their granules. Transporters mediate accumulation of these molecules in platelet granules and, on platelet activation, their translocation across the plasma membrane. The balance between transporter-mediated uptake and elimination of signaling molecules and drugs in platelets determines their intracellular concentrations and effects. Several members of the 2 major transporter families, ATP-binding cassette (ABC) transporters and solute carriers (SLCs), have been identified in platelets. An example of an ABC transporter is MRP4 (ABCC4), which facilitates ADP accumulation in dense granules. MRP4 is a versatile transporter, and various additional functions have been proposed, notably lipid mediator release and a role in aspirin resistance. Several other ABC proteins have been detected in platelets with functions in glutathione and lipid homeostasis. The serotonin transporter (SERT, SLC6A4) in the platelet plasma membrane represents a well-characterized example of the SLC family. Moreover, recent experiments indicate expression of OATP2B1 (SLCO2B1), a high affinity transporter for certain statins, in platelets. Changes in transporter localization and expression can affect platelet function and drug sensitivity. This review summarizes available data on the physiologic and pharmacologic role of transporters in platelets.

Platelets are derived from megakaryocytes. Despite being anucleate, they fulfill a multitude of functions. Platelets are not only key players in hemostasis and in vascular disease, they also contribute to inflammation, tumor angiogenesis, embryonic development, and immunologic responses.1,2  Platelets contain many biologically active molecules, such as factors triggering platelet aggregation, growth factors, and many other compounds, which are secreted on platelet activation. This function is highly dependent on their intracellular compartmentalization.

Platelets contain at least 3 types of intracellular granules, in which mediators are stored and concentrated, known as α, dense, and lysosomal granules.3  The α-granules mainly contain proteins critical to adhesion, such as von Willebrand factor, thrombospondin, and fibrinogen, as well as growth factors and protease inhibitors, clotting factors, and immunoglobulin G. Lysosomes hold a battery of hydrolytic enzymes, which are postulated to function in the elimination of circulating platelet aggregates and potentially also in host defense. Dense granules, such as lysosomes, are acidic organelles but, unlike the aforementioned organelles, contain extremely high concentrations of small molecules, especially ADP, ATP, serotonin, and calcium.3  Dense granule molecules participate in hemostasis in numerous ways, as ADP activates nearby platelets and serotonin causes vasoconstriction.

The biosynthesis of platelet-dense and α-granules is thought to occur in megakaryocytes through a common multivesicular intermediate body.4  However, the presence of plasma membrane proteins, such as GPIb, in the granule membranes suggests that these arise from both endogenous synthesis within the megakaryocyte as well as from fusion with endocytic vesicles during budding from the plasma membrane.5 

Platelet-dense granules are absent (or greatly reduced), and/or their contents are significantly reduced in a heterogeneous group of congenital platelets defects called δ-storage pool deficiencies (δ-SPD).6  These are associated with a moderate bleeding tendency. The most severe δ-SPD is Hermansky-Pudlak syndrome, a rare autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of melanosomes, platelet-dense granules, and lysosomes.7,8  Mutations in a variety of genes have been identified as causes for Hermansky-Pudlak syndrome, for example, in genes known to function in vesicle trafficking and in the biogenesis of lysosome-related organelles.9 

The accumulation of compounds, such as ADP, in high concentrations inside the dense granules points to their active transport. The identification of the ATP-binding cassette (ABC) protein ABCC4, better known as multidrug resistance protein 4 (MRP4), as a candidate transporter for adenine nucleotides in platelet-dense granules,10  represents a first step toward the elucidation of this important function of platelets. MRP4 is a markedly versatile transporter exhibiting a broad substrate specificity composed of a wide range of amphiphilic anions, including steroid conjugates and eicosanoids, as well as cyclic nucleotides and nucleotide analogues.11,12  Accordingly, several other tasks have been proposed for MRP4 in platelets taking into account that its localization can be shifted from granules to the plasma membrane on activation of the platelets and under certain pathophysiologic conditions.10,13,14  These include the release of lipid mediators15,16  as well as a role in aspirin resistance under certain conditions as in patients after coronary artery bypass graft surgery.14 

Detailed experiments address the transport of serotonin in platelets, especially its transport across the plasma membrane. Serotonin, which is released into circulation mainly from the enterochromaffin cells in the gut, is rapidly taken up by platelets and stored in platelet-dense granules, which constitute almost all total body circulating serotonin.17  Platelets have been used as models of neuronal transport of serotonin and also of several amino acid transmitters for many years.18,19  Furthermore, studies of the secretion mechanisms in platelets have indicated major similarities to neuronal transmitter release despite the fact that these cells have different origins.20  Neurons also contain small dense core vesicles that contain small molecules, such as serotonin taken up and concentrated from intracellular or extracellular pools, which resemble in many features platelet-dense granules.

An important emerging concept is that platelets may function as “long-haul truckers” not only for endogenous biologically active substances, such as serotonin, but also for a variety of drugs. Although platelets are small in size (only 2.0-5.0 μm in diameter),3  they represent a relatively large compartment for drugs considering their high numbers (normal range, 150-450 × 109 cells/L blood). In adults (5 L blood), the whole body platelet volume, including one-third splenic sequestration, accounts to approximately 20 mL (10 fL/platelet). This potential function of platelets is not well characterized, although it seems to be of major importance. All systemic drugs reach their targets via the bloodstream and come into contact with platelets; thereby, they can either be concentrated and stored within or be excluded from platelets, depending on the presence of uptake and export transporters in the platelet plasma membrane. In some cases, platelets also house the target structures, as the cyclo-oxygenase (COX)–1 enzyme,14  which is inhibited by aspirin and other nonsteroidal anti-inflammatory drugs, or the 3-hydroxy-3-methylglutaryl coenzyme A reductase,21  which represents the target of statins. As a result of transporter-mediated uptake, drugs can act on the target structures inside the platelets and provoke therapeutically positive effects or negative side effects. On the other hand, elimination of drugs from the platelet by export pumps can limit the effect of the drug and lead to drug resistance. Thus, because of their various functions, platelet transporters can either serve as drug targets or as drug delivery systems, and these functions can be greatly altered in the setting of thrombocytopenia or with inherited or acquired platelet defects.

The purpose of this review is to examine the state of the art in knowledge about transporters important in platelet function as well as in pharmacotherapy.

Two major protein superfamilies are involved in the transport of drugs as well as endogenous metabolites and signaling molecules: the ABC proteins with approximately 50 genes in humans grouped in 7 subfamilies,22,23  and the more than 300 solute carriers (SLCs) divided in 55 subfamilies.24,25  Members of both families have been identified in platelets (Table 1). In general, mammalian ABC transporters represent export pumps that bind and hydrolyse ATP, providing the energy for a unidirectional transport of a wide range of endogenous and exogenous compounds across membranes from the cytoplasm to the extracellular space or into cellular organelles, often against a concentration gradient.22,23  The typical structure of a functional (“full-size”) mammalian ABC transporter contains at least 2 clusters of usually 6 membrane-spanning segments as well as 2 nucleotide-binding domains (Figure 1A).22,23  In contrast, many SLC proteins function either by facilitating passive diffusion along the concentration gradient of the substrate (independently of energy input) or by cotransport and countertransport co-opting the concentration gradient of another solute. The structures of SLCs are often characterized by a cluster of 10 to 12 hydrophobic membrane-spanning segments (Figure 1B).24,25 

Figure 1

Typical membrane topologies predicted for ABC and SLC transporters. (A) Structure of MRP4 (ABCC4) consisting of 2 clusters of 6 membrane-spanning segments and 2 regions containing nucleotide binding domains (NBDs). (B) Structure of the serotonin uptake transport (SERT, SLC6A2) exhibiting a cluster of 12 membrane-spanning segments.

Figure 1

Typical membrane topologies predicted for ABC and SLC transporters. (A) Structure of MRP4 (ABCC4) consisting of 2 clusters of 6 membrane-spanning segments and 2 regions containing nucleotide binding domains (NBDs). (B) Structure of the serotonin uptake transport (SERT, SLC6A2) exhibiting a cluster of 12 membrane-spanning segments.

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The most prominent representative of the ABC proteins is ABCB1, better known as P-glycoprotein, which was originally identified by virtue of its ability to confer resistance to a range of structurally unrelated cytotoxic drugs in cancer cells (multidrug resistance). P-glycoprotein is expressed mainly in tissues with barrier function as in the gut or the blood-brain barrier,22  but not in platelets. Some features of P-glycoprotein, however, are shared by several members of the C-branch of the ABC family, the so-called MRPs.11  Members of this subfamily, such as MRP4, which is abundantly expressed in platelets, transport mainly amphiphilic anions, including many drugs or drug conjugates but also a number of endogenous signaling molecules, including arachidonate- and purine nucleotide-derived mediators.11  Other ABC transporters, especially of the A-branch, play an important role in the lipid homeostasis of cells, including platelets.26 

The superfamily of SLCs is composed of differed types of carriers for a huge spectrum of substrates, including nutrients, such as inorganic ions, sugars, amino acids, nucleotides, and vitamins, as well as drugs. Subfamilies of SLC for which members have been characterized within platelets include: the oligospecific Na+- and Cl-dependent monoamine neurotransmitter transporters (SLC6-family), with the serotonin transporter (SERT, SLC6A4) as a prominent member expressed in platelets; the vesicular amine transporter family (SLC18); the nucleoside-sugar transporter family (SLC35); as well as the multispecific organic anion transporting peptide family (SLC21/SLCO; Table 1). Members of the latter family have been recognized to play an important role in the distribution of certain drugs as statins. A member of this family, OATP2B1 (SLCO2B1), has also been characterized in platelets.21  Another SLC protein, the choline transporter-like protein 2 (CTL-2, SLC44A2) recently gained major attention in hematology when it was identified to carry the human neutrophil antigen (HNA)3a, one of the major antigens involved in transfusion-associated lung injury.27  This protein is also expressed in platelets.28 

Role of MRP4 (ABCC4) in platelets

The high concentration of ADP inside the platelet-dense granules (up to 0.6M) suggests the involvement of a primary active transport protein. A candidate protein mediating this active transport was found in MRP4. Besides its localization in the plasma membrane, MRP4 was demonstrated to be highly expressed in the membrane of dense granules (Figure 2A).10,13,14  Accordingly, an altered distribution of MRP4 was observed in platelets from a patient with Hermansky-Pudlak syndrome in which MRP4 was only detected in the plasma membrane because of the lack of dense granules.10  This intracellular localization distinguishes the MRP4 expression in platelets from that in other cell types, where it is localized mainly at the plasma membrane. It is conceivable that different splice variants of MRP4 are expressed in different tissues because at least 2 transcript variants of the human ABCC4/MRP4 gene exist that are predicted to encode proteins with distinct N-terminal extensions (reference sequences NM_005845.3 variant 1 and NM_001105515.1 shorter variant 2). Analysis of the MRP4 mRNA in platelets and mass spectrometry analysis of the protein,29  however, indicate that the platelet 190-kDa MRP4 glycoprotein corresponds to the long variant 1 expressed also in other tissues.30,31 

Figure 2

Proposed functions of MRP4 in mediator storage and drug resistance depending on its localization. (A) Role of MRP4 in mediator storage and release in normal resting and activated platelets. In resting platelets, MRP4 is mainly present in the membrane of dense granules10,13,14  and mediates sequestration of mediators and possibly other compounds into these organelles (left panel); in activated platelets, MRP4 among other granule membrane proteins is inserted into the plasma membrane on granule exocytosis and may then contribute to the release of a variety of compounds, including de novo generated lipid mediators (right panel). (B) Proposed role of MRP4 in aspirin resistance. As suggested by Mattiello et al,14  aspirin effect on platelets is little related to MRP4-mediated aspirin transport in normal platelets, although MRP4 may sequestrate a part of the drug into dense granules (left panel). In patients after coronary artery bypass graft surgery, however, MRP4 is up-regulated on the plasma membrane already in resting platelets and mediates active extrusion of aspirin from the cells resulting in an insufficient intracellular COX-1 inhibition by this drug14,33  (right panel).

Figure 2

Proposed functions of MRP4 in mediator storage and drug resistance depending on its localization. (A) Role of MRP4 in mediator storage and release in normal resting and activated platelets. In resting platelets, MRP4 is mainly present in the membrane of dense granules10,13,14  and mediates sequestration of mediators and possibly other compounds into these organelles (left panel); in activated platelets, MRP4 among other granule membrane proteins is inserted into the plasma membrane on granule exocytosis and may then contribute to the release of a variety of compounds, including de novo generated lipid mediators (right panel). (B) Proposed role of MRP4 in aspirin resistance. As suggested by Mattiello et al,14  aspirin effect on platelets is little related to MRP4-mediated aspirin transport in normal platelets, although MRP4 may sequestrate a part of the drug into dense granules (left panel). In patients after coronary artery bypass graft surgery, however, MRP4 is up-regulated on the plasma membrane already in resting platelets and mediates active extrusion of aspirin from the cells resulting in an insufficient intracellular COX-1 inhibition by this drug14,33  (right panel).

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The hypothesis that MRP4 is involved in the ADP storage in platelets is further supported by studies in patients with partial δ-SPDs, whose platelets are only deficient in ADP and not in serotonin.13  Based on the assumption that MRP4 is essential for the adenine nucleotide storage, one would expect that defects of MRP4 expression and localization are associated with decreased levels of adenine nucleotides in platelet-dense granules, but normal levels of other constituents, such as serotonin for which other transporters are involved. Two patients were identified who exhibited this rare phenotype of partial δ-SPD characterized by decreased platelet ADP content but normal serotonin levels. The MRP4 expression in the platelets of these patients was severely diminished.13  The underlying molecular defect leading to the diminished MRP4 expression in these platelets, however, has so far not been identified. A similar phenotype with selective adenine nucleotide deficiency was already previously observed in a dog model.32  Analyses of the MRP4 expression in platelets of patients with the more prevalent classic δ-SPD type, characterized by low adenine nucleotide and serotonin levels, revealed a different pattern. In these patients, MRP4 was found to be expressed in a quantitatively normal fashion, but its localization was significantly changed compared with normal platelets. In these patients, MRP4 seemed to be expressed only at the plasma membrane.13 

Interestingly, such a shift in the intracellular localization of MRP4 seems to occur also under other pathologic conditions. Recently, Mattiello et al reported that, compared with platelets from healthy volunteers, platelets from patients undergoing coronary artery bypass graft surgery exhibit increased amounts of MRP4, which was localized preferentially at the plasma membrane.14  In these patients, suboptimal platelet inhibition by aspirin (so-called aspirin resistance) is particularly common, and Mattiello et al hypothesized that the up-regulated MRP4 increases active extrusion of aspirin from platelet cytosol, resulting in less effective COX-1 inhibition14,33  (Figure 2B). This assumption is based on the following observations: aspirin reduced uptake of Fluo-cAMP, a potential MRP4 substrate, into dense granules of normal platelets and is released after thrombin activation of platelets, indicating that aspirin itself is accumulated in dense granules. Platelets from coronary artery bypass graft patients showed a high expression of MRP4 whose in vitro inhibition by dipyridamole or MK-571 enhanced aspirin entrapment and increased its effect on COX-1. Platelets derived from megakaryocytes transfected with MRP4 siRNA exhibited higher aspirin entrapment.14  Further studies are required to elucidate the role of MRP4 in aspirin transport and in the interindividual variations of platelet inhibition by aspirin that are also often observed in patients with acute coronary syndrome or diabetes.33,34 

When platelets are activated, granule integral membrane proteins become inserted into the plasma membrane on granule exocytosis.3  Thus, activated platelets exhibit an additional cohort of plasma membrane MRP4, which may alter platelet function by increased transport of various substrates. When inserted into the plasma membrane, MRP4 may also contribute to the export of a variety of lipid mediators, such as thromboxane A2 and leukotrienes (Figure 2A). In contrast to ADP and serotonin, these lipid mediators are supposed to be generated de novo on platelet activation. Because they exert their effects mainly extracellularly via interaction with membrane receptors, an efficient release from the cells is also required for these mediators.

It was first recognized for the 5-lipoxygenase product leukotriene C4 (LTC4) that its biosynthesis in leukocytes is followed by a distinct active export.35,36  MRP1 (ABCC1) was the first high-affinity transporter identified for LTC4,37 and its important role in LTC4 release from mast cells was confirmed in studies in Mrp1 knockout mice.38  ATP-dependent transport of this cysteinyl leukotriene was subsequently shown to be mediated also by other MRPs, including MRP3 (ABCC3)39  and MRP4.15  Although platelets lack 5-lipoxygenase activity, they contain LTC4 synthase40  and can produce LTC4 when supplied with LTA4 via transcellular mechanisms, and 3 LTC4 transporters, MRP1, MRP3, and MRP4, are expressed in platelets, which makes it likely that platelets play an important role in LTC4 homeostasis.

Primary prostaglandins (PGs) such as PGE2 and thromboxane A2, have been formerly assumed to diffuse passively from the cell, despite being poorly membrane permeable. Reid et al30  and Rius et al41  demonstrated, however, that prostaglandins, including thromboxane B2, are actively transported by MRP4 and that this transport is inhibited by a number of nonsteroidal anti-inflammatory drugs, such as ibuprofen and indomethacin.30 

Another immune-modulating lipid mediator released by platelets on thrombin stimulation is sphingosine-1-phosphate (S-1-P). Platelet-derived S-1-P modulates the chemotaxis of monocytes and is involved in inflammatory processes.42  The release of S-1-P was found to depend on platelet thromboxane formation and activation of the thromboxane receptor.16  The actual release process probably also involves a member of the MRP family.16  It was suggested that MRP1 mediates S-1-P export in mast cells.43  Secretion of S-1-P from human platelets was blocked by MK571,16  a cysteinyl leukotriene analog, which was originally identified as a specific inhibitor for MRP137  but interferes also with MRP4.10,15  S-1-P excretion by platelets was also inhibited by dipyridamole and indomethacin,16  which are known to inhibit preferentially MRP4.10,30  This suggests that the release of S-1-P from platelets also involves members of the MRP family, preferentially MRP4.

Inserted in the plasma membrane, MRP4 may also extrude cyclic nucleotides, such as cAMP and cGMP,10,12,44  which are both critical inhibitory intracellular second messengers regulating fundamental processes in platelets.45  The cellular levels of these mediators are controlled by the action of phosphodiesterases, which have been also suggested as targets in antiplatelet treatment,46  as well as by active secretion into the extracellular space, which may provide also extracellular purine-based mediators for paracrine functions.

From a therapeutic perspective, there are thus several aspects regarding MRP4 that provide reasons for its targeting in use of MRP4 inhibitors for antiplatelet therapy. MRP4 transport is inhibited by dipyridamole, which, however, has other effects, such as inhibition of phosphodiesterases.46  More specific (but as yet undeveloped) compounds would be a very interesting option to interfere selectively with platelet ADP storage and possibly also release of lipid mediators.

In addition to physiologic and pathophysiologic regulation, genetic variations may account for variable MRP4 function. The ABCC4/MRP4 gene is highly polymorphic with at least 25 nonsynonymous single nucleotide polymorphisms; however, the influence of these on MRP4 expression and function in vivo remains to be established.31  Interestingly, the ABCC4/MRP4 gene was one of the 68 genomic loci, which were identified as putative regulators of platelet formation in a recently published meta-analysis of genome-wide association studies for platelet count and volume.47 

Mrp4(−/−) mice have been generated and characterized mainly with respect to their susceptibility toward nucleoside analogues.48  They exhibit no obvious bleeding tendency; however, extrapolating these observations to humans is problematic because of interspecies differences in the properties of the transporter and in the overall hemostatic process and compensatory mechanisms.

MRP1 (ABCC1) and MRP3 (ABCC3)

Reports on the expression of MRP1 in platelets had been controversial.15,49  The presence of MRP1 in platelet membranes could be proven by use of 2D-nanoLC-MS/MS,29  but in a significantly lower amount compared with MRP4. Both MRP1 and MRP4 are able to contribute to the transport of LTC4 as well as to platelet glutathione homeostasis because both MRPs mediate cotransport of a variety of endogenous and exogenous compounds with reduced glutathione.11,15,50  MRP1 exports in addition oxidized glutathione (glutathione disulfate).51  Another candidate transporter for LTC4 that is present in platelet membranes is MRP3, which also transports cysteinyl leukotrienes, although with a lower affinity as observed with MRP1.39  Interestingly, the expression of MRP3 and MRP4 increases during differentiation of hematopoietic progenitor cells toward megakaryocytes, suggesting that the expression of these proteins may be particularly important for platelet function.29  MRP1 and MRP3 are also known to confer resistance to a number of cytotoxic agents, such as etoposide.11  Thus, they may also play a role in resistance of platelets against toxins and can determine the action of several amphiphilic drugs on platelet function.

ABCA and ABCB transporters

Transcripts of several members of the ABCA family, such as ABCA3, ABCA4, ABCA6, ABCA7, and ABCA9, have been detected in human platelets.29  ABCA7 was shown to be preferentially expressed in platelets and localized at the plasma membrane of rat and human platelets.29,52  ABCA proteins are typically associated with lipid translocation processes in membranes. Two types of intramembrane lipid translocators can be defined: flippases, which translocate lipids from the outer leaflet to the inner leaflet of the membrane; and floppases, which mediate the reverse process (ie, translocation from the inner to the outer leaflet of the membrane bilayer).53  Such membrane remodeling processes also play an important role in platelet function, especially during secondary hemostasis. The flopping of phosphatidylserine from the inner to outer membrane leaflet during platelet activation, together with microparticle shedding, provides a catalytic surface for the assembly of coagulation complexes.54,55  There is a rare platelet defect, the Scott syndrome,56  which underscores the importance of this pathway. In these patients, although primary hemostatic function of platelets is intact, the platelets do not support the assembly of coagulation complexes because of defective scrambling of membrane phospholipids.56  In addition, there exists an inverse condition, the Stormorken syndrome, in which platelets constitutively expose phosphatidylserine on the external leaflet of their plasma membrane.57 

Two protein classes are thought to be involved in membrane remodeling: a nonspecific and energy-independent family of so-called scramblases58  and ABC transporters, especially of the A- and B-branch. ABCA1, which is involved in cholesterol efflux from cells and in phagocytosis, and which is mutated in Tangier dyslipidemia (absence of high-density lipoprotein-cholesterol from plasma),59,60  has been considered also to play a role in Scott syndrome. This hypothesis is based on the observation that targeted deletion of the corresponding gene locus resulted in a phenotype evocative of partial Scott syndrome,61  and a mis-sense mutation in the ABCA1 gene was identified in a Scott syndrome patient.62  However, the expression of ABCA1 in platelets has not been established so far.

ABCA7, which has been identified in platelets, however, shares several features with ABCA1. ABCA7 also mediates the formation of high-density lipoprotein when exogenously transfected and expressed and was also reported to relate to the phagocytotic function of cells.63  Genetic variants of the ABCA7 gene have been found to be associated with Alzheimer disease.64  ABCB4, also known as MDR2/3 (Mdr2 in rodents, MDR3 in humans), represents another floppase identified in the platelet plasma membrane.29  This finding is surprising because the expression and function of MDR3 were thought to be limited to the canalicular membrane of hepatocytes.65  Here, MDR3 “flops” phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane, thereby making this phospholipid available for extraction into the canalicular lumen by bile salts.66  Mutations in the ABCB4/MDR3 gene cause progressive familial intrahepatic cholestasis.66  However, so far none of the ABCA and ABCB transporters has been explicitly confirmed as a floppase for PS. The interaction of platelet microparticles with the endothelium and leukocytes in addition triggers inflammation. Thus, the lipid translocators in platelets may have an important role in thrombosis and in inflammation.

Besides their role in plasma membrane remodeling, MDR3 and ABCA proteins may be involved in the release of lipid mediators as lysophosphatidic acid and S1-P from platelets. Lysophosphatidic acid is a bioactive lipid that binds to cell surface G-protein-coupled receptors to regulate cell growth, differentiation, and development.67  In the cardiovascular system, lysophosphatidic acid alters the endothelial barrier function and is a weak platelet agonist.68,69  In addition, it was proposed that members of the ABCA subfamily are involved in the transport of S-1-P,52  especially ABCA7. Furthermore, ABCAs and MDR3 may function in the defense of platelets against highly lipophilic compounds.

Serotonin transporters

Serotonin (5-hydroxytryptamine [5-HT]) is best known for its role as neurotransmitter involved in mood disorders.18  However, serotonin is also stored in platelets and, when released, promotes platelet aggregation via the serotonin receptor (5-HT2A) on platelets.17  Moreover, it exhibits strong vasoactive properties, possibly through stimulation of serotonin receptors on endothelial cells and through nitric oxide production.70  Recently, it was also shown that serotonin strongly induces extracellular matrix synthesis in interstitial fibroblasts and promotes tissue fibrosis.71 

Serotonin storage in platelets results from a 2-step process: (1) the uptake across the platelet plasma membrane; and (2) the transport across the dense granule membrane. The uptake of serotonin into the platelet cytosol is mediated by SERT (also called 5-HTT). The cDNA of human SERT has been cloned, and the gene (SLC6A4) has been assigned to the human chromosome 17.72,73  Expression of SERT was characterized in different tissues, including brain and platelets. Thereby, the transport protein appears identical in brain and platelets.74  SERT belongs to the SLC6 gene family of Na+/Cl-dependent neurotransmitter transporter proteins.75  The actual uptake process involves the binding of serotonin to its recognition site within the transporter and its transport across the membrane together with an Na+ ion. A second step involves the translocation of a K+ ion across the membrane to the outside of the cell. This requirement for K+ countertransport is unique for SERT within the SLC6 family.76  Because both tricyclic antidepressants and the newer selective serotonin reuptake inhibitors (SSRIs) bind to SERT and inhibit serotonin uptake, the importance of understanding the biochemical characteristics of this transporter has long been appreciated.18  SSRIs block the reuptake of serotonin into neurons as well as the uptake into platelets; thus, platelets were used as model for monitoring the effect of antidepressants.77,78 

In addition, platelets exhibit uptake mechanisms for several amino acid transmitters, among them γ-aminobutyric acid, glutamate, aspartate, and glycine, and characteristics of the platelet uptake functions resemble those of the uptake in the central nervous system,19  qualifying platelets as a favored model system in neurology (Figure 3).

Figure 3

Transport and storage of monoamine mediators in neurons and platelets. SERT mediates reuptake of serotonin (5-HT) in neurons as well as uptake into platelets and is inhibited by tricyclic antidepressants and SSRIs.18,79  The storage in dense vesicles is supposed to be mediated by the VMAT (SLC18A).85,87  The energy for this transport is provided by the function of the vacuolar H+-ATPase. 5-HT-R indicates serotonin receptor.

Figure 3

Transport and storage of monoamine mediators in neurons and platelets. SERT mediates reuptake of serotonin (5-HT) in neurons as well as uptake into platelets and is inhibited by tricyclic antidepressants and SSRIs.18,79  The storage in dense vesicles is supposed to be mediated by the VMAT (SLC18A).85,87  The energy for this transport is provided by the function of the vacuolar H+-ATPase. 5-HT-R indicates serotonin receptor.

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Prolonged intake of SSRIs can lead to a significant decrease in platelet serotonin.17,77  However, bleeding problems are rarely observed in SSRI-treated patients. This may be the result of the postulated prothrombotic disturbance in untreated depression accompanied with an increased cardiovascular risk.79  Although under normal conditions the bleeding risk induced by SSRIs is low, they can increase the risk for bleeding in major surgery.80  Serotonin promoter polymorphisms have been linked to major depressive disorders as well as to an increased risk of new cardiac events after acute myocardial infarction.81,83  SERT knockout mice have been generated and are vital, but platelet function has not been studied in detail.84 

Less is known about the transport of serotonin across the dense granule membrane, which is supposed to be mediated by a reserpine-sensitive vesicular monoamine transporter (VMAT, SLC18), which is also present in the secretory vesicles of monoaminergic neurons and neuroendocrine cells in the gut.85,86  This transport is driven by an electrochemical proton gradient across the vesicular membrane, which is generated by the vacuolar H+-ATPase and is potently inhibited by reserpine and tetrabenazine.85,86  In mammals, 2 closely related isoforms of the monoamine transporter, termed VMAT1 and VMAT2 (SLC18A1 and SLC18A2), respectively, have been identified, which are located on different vesicle subtypes.85,86  VMAT2 has been shown to be expressed mainly in synaptic dense core vesicles, which resemble platelet-dense granules.87  Both VMATs transport serotonin, dopamine, epinephrine, and norepinephrine but differ in their substrate preferences and affinities.

Transporters for nutrients and metabolic intermediates

Platelets, like other cells, need uptake transporters for nutrients. For example, platelets accumulate ascorbic acid through the expression of SVCT 2 (SLC23A2), a member of the Na+-dependent ascorbic acid transporter family (SLC23).88  Interestingly, platelets can compensate for fluctuations in ascorbate levels by modulating the expression of SVCT2 at the translational level.89  Platelets, although anucleate, contain RNA, some of which is translated into proteins, including transporters, according to requirements.89  SLC proteins also often transport metabolites from the cytosol into intracellular organelles. Interestingly, mutations in the Slc35d3 gene have been associated with platelet-dense granule defects in a murine model.90  Slc35d3 is a member of the SLC35 nucleotide sugar transporter family. Members of this family are characterized as antiporters, transporting nucleotide sugars from the cytosol into the lumen of the Golgi apparatus and/or the endoplasmic reticulum.91  In platelets, the dense tubular system represents residual endoplasmic reticulum of the parent megakaryocytes. However, the actual localization of this transporter in platelets as well as its role in platelet-dense granule dysfunction has not been further elucidated.

OATPs

Nutrients and drugs can share common transporters. The relevance of platelet uptake transporters for the distribution and action of drugs has been well demonstrated for statins. Available evidence supports the notion that the beneficial effects of statins on hypercholesterolemia-associated diseases, such as acute coronary syndrome, stroke, and atherosclerotic lesions, are attributable not only to their low-density lipoprotein-lowering effect but also to additional mechanisms of action.92  These “pleiotropic” effects include the stabilization of arterial plaques, normalization of endothelial functions, anti-inflammatory effects, and inhibition of platelet thrombus formation.93  On the molecular level, pleiotropic effects of statins have been attributed to the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase in nonhepatic structures.94  This inhibition results in diminished biosynthesis of mevalonate, the precursor to cholesterol, and also to hydrophobic prenyl moieties, which are essential for proper sorting and function of several cell membrane-associated proteins, as receptors.95  If the modification of platelet function by statins proceeds via inhibition of platelet 3-hydroxy-3-methylglutaryl coenzyme A reductase, uptake of these drugs into platelets is a prerequisite. In the liver, the prime target organ for statins, uptake of statins, was shown to be mediated by transporters of the organic anion-transporting polypeptide (OATP/SLCO) family, mainly OATP1B1.96  A related transporter, OATP2B1, was detected in platelets and localized to the plasma membrane.21  OATP2B1 was shown before to transport atorvastatin and rosuvastatin as high-affinity substrates.97,98  Accordingly, an active transport of atorvastatin into platelets could be demonstrated, which was inhibited by the known OATB2B1 substrate estrone sulfate and vice versa.21  As a consequence of OATP2B1-mediated uptake of atorvastatin, a significant reduction of thrombin-induced Ca2+ mobilization in platelets was observed, which could be mechanistically explained by reduced prenylation of signal proteins. The effect was reversed by addition of mevalonate, the precursor to prenyl moieties as well as in presence of estrone sulfate, which competitively inhibits atorvastatin uptake.21 

Besides statins, drugs and metabolites such as dehydroepiandrosterone-3-sulfate or estrone sulfate, which are described as OATP2B1 substrates, could be taken up into platelets by this transporter. For example, dehydroepiandrosterone-3-sulfate administration improves platelet superoxide dismutase activity, which protects cells against oxidative damage.99  The expression of OATP2B1 is probably only one example of how transporters in platelets influence effects of drugs, or vice versa, how drugs affect platelet biology. The list of drug uptake transporters in platelets is expected to grow rapidly, as this aspect of platelet transporters is addressed more intensively.

In conclusion, platelets contain a variety of transporters in their plasma membrane as well as within the membranes of their intracellular compartments (summarized in Figure 4). These proteins play a vital role in the storage and release of endogenous signaling molecules, implicating them as relevant structures for certain platelet function disorders as it has been shown for storage pool deficiencies. Platelets may serve also as vehicles that pick up compounds from various regions in the organism, including the gut, and transport them to their target organs. This would add new aspects to the role of platelets in many disorders, including host defense and immunology.100 

Figure 4

Platelet transporters and their proposed functions at a glance. Platelets express a variety of SLC and ABC transporters, which are located in the plasma membrane as well as in the membranes of intracellular compartments,such as the dense (δ) and α (α) granules, and in other intracellular membrane systems, such as the dense tubular system (DTS; for details and references, see Table 1). They play a vital role in the uptake, sequestration, and release of mediators involved in platelet function. With respect to pharmacotherapy, the platelet represents a pharmacokinetic microcompartment, in which the interplay between uptake and elimination transporters determines intracellular drug concentrations.

Figure 4

Platelet transporters and their proposed functions at a glance. Platelets express a variety of SLC and ABC transporters, which are located in the plasma membrane as well as in the membranes of intracellular compartments,such as the dense (δ) and α (α) granules, and in other intracellular membrane systems, such as the dense tubular system (DTS; for details and references, see Table 1). They play a vital role in the uptake, sequestration, and release of mediators involved in platelet function. With respect to pharmacotherapy, the platelet represents a pharmacokinetic microcompartment, in which the interplay between uptake and elimination transporters determines intracellular drug concentrations.

Close modal

Transporters are also potential new targets for pharmacologic inhibition of platelet function. Inhibiting a transporter instead of a receptor provides attractive options. On the one hand, the effects are long lasting and relatively robust even in patients with moderate compliance; and on the other hand, the drug effect can be counteracted immediately by transfusion of platelet concentrates, as the transfused platelets contain the substrates of the respective transporter. From a more pharmacologic point of view, platelets represent pharmacokinetic micro-compartments, in which the combination of uptake and elimination transport, possibly together with intracellular metabolism, determines pharmacokinetics of drugs. Transporters can be specifically used to direct antiplatelet drugs to target structures inside the platelets. Probably more important, many non-antiplatelet drugs may interfere with the physiologic substrates of these transporters in platelets and may in this way affect platelet function and modulate their hemostatic capacity. A better understanding of these mechanisms may help to recognize potential prothrombotic or prohemorrhagic effects of drugs. Finally, platelets may influence pharmacotherapy of possibly many drugs and accordingly contribute to interindividual variation in drug response. Therefore, a detailed understanding of the expression, function, and regulation of transporters in platelets will add to a better understanding of platelet biology and in many ways may result in improved therapeutic options.

The authors thank Theodore Warkentin (Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON) for expert proofreading of the manuscript.

This work was supported by Deutsche Forschungsgemeinschaft, Germany (grants JE234/4-1 and SFB/TR19), and by the GANI-MED project (the Greifswald Approach to Individualized Medicine), funded by the Federal Ministry of Education and Research, Germany; and by the Center for Immune Reactions in Cardiovascular Disease, funded by the Federal Ministry of Education and Research, Germany.

Contribution: G.J. wrote the paper and designed the figures; and A.G. and H.K.K. edited the manuscript and provided conceptual insights.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Gabriele Jedlitschky, Institut für Pharmakologie, Center of Drug Absorption and Transport, Ernst-Moritz-Arndt-Universität Greifswald, D-17487 Greifswald, Germany; e-mail: jedlits@uni-greifswald.de; and Andreas Greinacher, Institut für Immunologie und Transfusionsmedizin, Ernst Moritz-Arndt-Universität Greifswald, 17487 Greifswald, Germany; e-mail: greinach@uni-greifswald.de.

1
Leslie
M
Cell biology. Beyond clotting: the powers of platelets.
Science
2010
328
5978
562
564
2
Krauel
K
Pötschke
C
Weber
C
et al
Platelet factor 4 binds to bacteria, inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia.
Blood
2011
117
4
1370
1378
3
White
JG
Colman
RW
Hirsch
J
Marder
VJ
Salzman
EW
Anatomy and structural organization of the platelet.
Hemostasis and Thrombosis: Basic Principles and Clinical Practice
1994
3rd Ed
Philadelphia, PA
Lippincott
397
413
4
Youssefian
T
Cramer
EM
Megakaryocyte dense granule components are sorted in multivesicular bodies.
Blood
2000
95
12
4004
4007
5
Youssefian
T
Masse
JM
Rendu
F
Guichard
J
Cramer
EM
Platelet and megakaryocyte dense granules contain glycoproteins Ib and IIb-IIIa.
Blood
1997
89
11
4047
4057
6
Cattaneo
M
Inherited, platelet-based bleeding disorders.
J Thromb Haemost
2003
12
7
1628
1636
7
Hermansky
F
Pudlak
P
Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow.
Blood
1959
14
2
162
169
8
Huizing
M
Gahl
WA
Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes.
Curr Mol Med
2002
2
5
451
467
9
Wei
ML
Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function.
Pigment Cell Res
2006
19
1
19
42
10
Jedlitschky
G
Tirschmann
K
Lubenow
LE
et al
The nucleotide transporter MRP4 (ABCC4) is highly expressed in human platelets and present in dense granules, indicating a role in mediator storage.
Blood
2004
104
12
3603
3610
11
Deeley
RG
Westlake
C
Cole
SP
Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins.
Physiol Rev
2006
86
3
849
899
12
Russel
FG
Koenderink
JB
Masereeuw
R
Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules.
Trends Pharmacol Sci
2008
29
4
200
207
13
Jedlitschky
G
Cattaneo
M
Lubenow
LE
et al
Role of MRP4 (ABCC4) in platelet adenine nucleotide-storage: evidence from patients with delta-storage pool deficiencies.
Am J Pathol
2010
176
3
1097
1103
14
Mattiello
T
Guerriero
R
Lotti
LV
et al
Aspirin extrusion from human platelets through multidrug resistance protein-4-mediated transport evidence of a reduced drug action in patients after coronary artery bypass grafting.
J Am Coll Cardiol
2011
58
7
752
761
15
Rius
M
Hummel-Eisenbeiss
J
Keppler
DJ
ATP-dependent transport of leukotrienes B4 and C4 by the multidrug resistance protein ABCC4 (MRP4).
Pharmacol Exp Ther
2008
324
1
86
94
16
Ulrych
T
Böhm
A
Polzin
A
et al
Release of sphingosine-1-phosphate from human platelets is dependent on thromboxane formation.
J Thromb Haemost
2011
9
4
790
798
17
Maurer-Spurej
E
Pittendreigh
C
Solomons
K
The influence of selective serotonin reuptake inhibitors on human platelet serotonin.
Thromb Haemost
2004
91
1
119
128
18
Owens
MJ
Nemeroff
CB
Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter.
Clin Chem
1994
40
2
288
295
19
Rainesalo
S
Keränen
T
Saransaari
P
Honkaniemi
J
GABA and glutamate transporters are expressed in human platelets.
Brain Res Mol Brain Res
2005
141
2
161
165
20
Reed
GL
Fitzgerald
ML
Polgar
J
Molecular mechanisms of platelet exocytosis: insights into the “secrete” life of thrombocytes.
Blood
2000
96
10
3334
3342
21
Niessen
J
Jedlitschky
G
Grube
M
et al
Human platelets express organic anion-transporting peptide 2B1, an uptake transporter for atorvastatin.
Drug Metab Dispos
2009
37
5
1129
1137
22
Borst
P
Elferink
RO
Mammalian ABC transporters in health and disease.
Annu Rev Biochem
2002
71
537
592
23
Vasiliou
V
Vasiliou
K
Nebert
DW
Human ATP-binding cassette (ABC) transporter family.
Hum Genomics
2009
3
3
281
290
24
He
L
Vasiliou
K
Nebert
DW
Analysis and update of the human solute carrier (SLC) gene superfamily.
Hum Genomics
2009
3
2
195
206
25
Hediger
MA
Romero
MF
Peng
JB
Rolfs
A
Takanaga
H
Bruford
EA
The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins.
Pflugers Arch
2004
447
5
465
468
26
Albrecht
C
Viturro
E
The ABCA subfamily-gene and protein structures, functions and associated hereditary diseases.
Pflugers Arch
2007
453
5
581
589
27
Greinacher
A
Wesche
J
Hammer
E
et al
Characterization of the human neutrophil alloantigen-3a.
Nat Med
2010
16
1
45
48
28
Wesche
J
Jehmlich
U
Schwertz
H
et al
Expression of the choline transporter like protein 2 (CTL2) in platelets.
Hämostaseologie
2011
Accessed September 16, 2011
A78
29
Niessen
J
Jedlitschky
G
Grube
M
et al
Expression of ABC-type transport proteins in human platelets.
Pharmacogenet Genomics
2010
20
6
396
400
30
Reid
G
Wielinga
P
Zelcer
N
et al
The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs.
Proc Natl Acad Sci U S A
2003
100
16
9244
9249
31
Gradhand
U
Lang
T
Schaeffeler
E
et al
Variability in human hepatic MRP4 expression: influence of cholestasis and genotype.
Pharmacogenomics J
2007
8
1
42
52
32
Callan
MB
Bennett
JS
Phillips
DK
et al
Inherited platelet delta-storage pool disease in dogs causing severe bleeding: an animal model for a specific ADP deficiency.
Thromb Haemost
1995
74
3
949
953
33
Eikelboom
JW
Hankey
GJ
Overexpression of the multidrug resistance protein-4 transporter in patients undergoing coronary artery bypass graft surgery a cause of aspirin resistance?
J Am Coll Cardiol
2011
58
7
762
764
34
Hankey
GJ
Eikelboom
JW
Aspirin resistance.
Lancet
2006
367
9510
606
617
35
Lam
BK
Owen
WF
Jr
Austen
KF
Soberman
RJ
The identification of a distinct export step following the biosynthesis of leukotriene C4 by human eosinophils.
J Biol Chem
1989
264
22
12885
12889
36
Schaub
T
Ishikawa
T
Keppler
D
ATP-dependent leukotriene export from mastocytoma cells.
FEBS Lett
1991
279
1
83
86
37
Leier
I
Jedlitschky
G
Buchholz
U
Cole
SP
Deeley
RG
Keppler
D
The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates.
J Biol Chem
1994
269
45
27807
27810
38
Wijnholds
J
Evers
R
van Leusden
MR
et al
Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein.
Nat Med
1997
3
11
1275
1279
39
Hirohashi
T
Suzuki
H
Sugiyama
Y
Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3).
J Biol Chem
1999
274
21
15181
15185
40
Tornhamre
S
Sjölinder
M
Lindberg
Å
et al
Demonstration of leukotriene C4 synthase in platelets and species distribution of the enzyme activity.
Eur J Biochem
1998
251
1
227
235
41
Rius
M
Thon
WF
Keppler
D
Nies
AT
Prostanoid transport by multidrug resistance protein 4 (mrp4/abcc4) localized in tissues of the human urogenital tract.
J Urol
2005
174
6
2409
2414
42
Rivera
R
Chun
J
Biological effects of lysophospholipids.
Rev Physiol Biochem Pharmacol
2008
160
25
46
43
Mitra
P
Oskeritzian
CA
Payne
SG
Beaven
MA
Milstien
S
Spiegel
S
Role of ABCC1 in export of sphingosine-1-phosphate from mast cells.
Proc Natl Acad Sci U S A
2006
103
44
16394
16399
44
Chen
ZS
Lee
K
Kruh
GD
Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4: resistance to 6-mercaptopurine and 6-thioguanine.
J Biol Chem
2001
276
36
33747
33754
45
Daniel
J
Ashby
B
Pulcinelli
F
Gresele
P
Page
C
Fuster
V
Vermylen
J
Platelet signaling: cAMP and cGMP.
Platelets in Thrombotic and Non-Thrombotic Disorders
2002
Cambridge, United Kingdom
Cambridge University Press
290
304
46
Gresele
P
Momi
S
Falcinelli
E
Antiplatelet therapy: phosphodiesterase inhibitors.
Br J Clin Pharmacol
2011
72
4
634
646
47
Gieger
C
Radhakrishnan
A
Cvejic
A
et al
New gene functions in megakaryopoiesis and platelet formation.
Nature
2011
480
7376
201
208
48
Kruh
GD
Belinsky
MG
Gallo
JM
Lee
K
Physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 as determined from recent studies on gene disrupted mice.
Cancer Metastasis Rev
2007
26
1
5
14
49
Sjölinder
M
Tornhamre
S
Claesson
HE
Hydman
J
Lindgren
J
Characterization of a leukotriene C4 export mechanism in human platelets: possible involvement of multidrug resistance-associated protein 1.
J Lipid Res
1999
40
3
439
446
50
Rius
M
Nies
AT
Hummel-Eisenbeiss
J
Jedlitschky
G
Keppler
D
Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane.
Hepatology
2003
38
2
374
384
51
Leier
I
Jedlitschky
G
Buchholz
U
et al
ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump.
Biochem J
1996
314
2
433
437
52
Sasaki
M
Shoji
A
Kubo
Y
Nada
S
Yamaguchi
A
Cloning of rat ABCA7 and its preferential expression in platelets.
Biochem Biophys Res Commun
2003
304
4
777
782
53
Daleke
DL
Regulation of transbilayer plasma membrane phospholipid asymmetry.
J Lipid Res
2003
44
2
233
242
54
Handin
RI
Inherited platelet disorders.
Hematology
2005
2005
1
396
402
55
Morel
O
Morel
N
Freyssinet
JM
Toti
F
Platelet microparticles and vascular cells interactions: a checkpoint between the haemostatic and thrombotic responses.
Platelets
2008
19
1
9
23
56
Zwaal
RF
Comfurius
P
Bevers
EM
Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids.
Biochim Biophys Acta
2004
1636
2
119
128
57
Stormorken
H
Holmsen
H
Sund
R
et al
Studies on the haemostatic defect in a complicated syndrome: an inverse Scott syndrome platelet membrane abnormality?
Thromb Haemost
1995
74
5
1244
1251
58
Zhou
Q
Zhao
J
Stout
JG
Luhm
RA
Wiedmer
T
Sims
PJ
Molecular cloning of human plasma membrane phospholipid scramblase: a protein mediating transbilayer movement of plasma membrane phospholipids.
J Biol Chem
1997
272
29
18240
18244
59
Bodzioch
E
Orso
J
Klucken
T
et al
The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.
Nat Genet
1999
22
4
347
351
60
Rust
S
Rosier
M
Funke
H
et al
Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.
Nat Genet
1999
22
4
352
355
61
Hamon
Y
Broccardo
C
Chambenoit
O
et al
ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine.
Nat Cell Biol
2000
2
7
399
406
62
Albrecht
C
McVey
JH
Elliott
JI
et al
A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome.
Blood
2005
106
2
542
549
63
Tanaka
N
Abe-Dohmae
S
Iwamoto
N
Yokoyama
S
Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system.
J Atheroscler Thromb
2011
18
4
274
281
64
Hollingworth
P
Harold
D
Sims
R
et al
Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.
Nat Genet
2011
43
5
429
435
65
Smit
JJ
Schinkel
AH
Mol
CA
et al
Tissue distribution of the human MDR3 P-glycoprotein.
Lab Invest
1994
71
5
638
649
66
Oude Elferink
RP
Paulusma
CC
Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein).
Pflugers Arch
2007
453
5
601
610
67
Choi
JW
Herr
DR
Noguchi
K
et al
LPA receptors: subtypes and biological actions.
Annu Rev Pharmacol Toxicol
2010
50
157
186
68
Siess
W
Zangl
KJ
Essler
M
et al
Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions.
Proc Natl Acad Sci U S A
1999
96
12
6931
6936
69
Pamuklar
Z
Lee
JS
Cheng
HY
et al
Individual heterogeneity in platelet response to lysophosphatidic acid: evidence for a novel inhibitory pathway.
Arterioscler Thromb Vasc Biol
2008
28
3
555
561
70
Srikiatkhachorn
A
Suwattanasophon
C
Ruangpattanatawee
U
Phansuwan-Pujito
P
2002-Wolff Award. 5-HT2A receptor activation and nitric oxide synthesis: a possible mechanism determining migraine attacks.
Headache
2002
42
7
566
574
71
Dees
C
Akhmetshina
A
Zerr
P
et al
Platelet-derived serotonin links vascular disease and tissue fibrosis.
J Exp Med
2011
208
5
961
972
72
Ramamoorthy
S
Bauman
AL
Moore
KR
et al
Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization.
Proc Natl Acad Sci U S A
1993
90
6
2542
2546
73
Lesch
KP
Wolozin
BL
Estler
HC
Murphy
DL
Riederer
P
Isolation of a cDNA encoding the human brain serotonin transporter.
J Neural Transm Gen Sect
1993
91
1
67
72
74
Lesch
KP
Wolozin
BL
Murphy
DL
Reiderer
P
Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter.
J Neurochem
1993
60
6
2319
2322
75
Chen
NH
Reith
ME
Quick
MW
Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6.
Pflugers Arch
2004
447
5
519
531
76
Rudnick
G
Clark
J
From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters.
Biochim Biophys Acta
1993
1144
3
249
263
77
Bakish
D
Cavazzoni
P
Chudzik
J
Ravindran
A
Hrdina
PD
Effects of selective serotonin reuptake inhibitors on platelet serotonin parameters in major depressive disorder.
Biol Psychiatry
1997
41
2
184
190
78
Neuger
J
Wistedt
B
Sinner
B
Aberg-Wistedt
A
Stain-Malmgren
R
The effect of citalopram treatment on platelet serotonin function in panic disorders.
Int Clin Psychopharmacol
2000
15
2
83
91
79
Maurer-Spurej
E
Serotonin reuptake inhibitors and cardiovascular diseases: a platelet connection.
Cell Mol Life Sci
2005
62
2
159
170
80
Andrade
C
Sandarsh
S
Chethan
KB
Nagesh
KS
Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms.
J Clin Psychiatry
2010
71
12
1565
1575
81
Greenberg
BD
Tolliver
TJ
Huang
SJ
Li
Q
Bengel
D
Murphy
DL
Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets.
Am J Med Genet
1999
88
1
83
87
82
Nakatani
D
Sato
H
Sakata
Y
et al
Influence of serotonin transporter gene polymorphism on depressive symptoms and new cardiac events after acute myocardial infarction.
Am Heart J
2005
150
4
652
658
83
Sue
S
Zhao
J
Bremner
JD
et al
Serotonin transporter gene, depressive symptoms, and interleukin-6.
Circ Cardiovasc Genet
2009
2
6
614
620
84
Bengel
D
Murphy
DL
Andrews
AM
et al
Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice.
Mol Pharmacol
1998
53
4
649
655
85
Erickson
JD
Eiden
LE
Hoffman
BJ
Expression cloning of a reserpine-sensitive vesicular monoamine transporter.
Proc Natl Acad Sci U S A
1992
89
22
10993
10997
86
Erickson
JD
Schafer
MK
Bonner
TI
Eiden
LE
Weihe
E
Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter.
Proc Natl Acad Sci U S A
1996
93
10
5166
5171
87
Nirenberg
MJ
Liu
Y
Peter
D
Edwards
RH
Pickel
VM
The vesicular monoamine transporter 2 is present in small synaptic vesicles and preferentially localizes to large dense core vesicles in rat solitary tract nuclei.
Proc Natl Acad Sci U S A
1995
92
19
8773
8777
88
Takanaga
H
Mackenzie
B
Hediger
MA
Sodium-dependent ascorbic acid transporter family SLC23.
Pflugers Arch
2004
447
5
677
682
89
Savini
I
Catani
MV
Arnone
R
et al
Translational control of the ascorbic acid transporter SVCT2 in human platelets.
Free Radic Biol Med
2007
42
5
608
616
90
Chintala
S
Tan
J
Gautam
R
et al
The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules.
Blood
2007
109
4
1533
1540
91
Ishida
N
Kawakita
M
Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35).
Pflugers Arch
2004
447
5
768
775
92
Vaughan
CJ
Gotto
AM
Jr
Basson
CT
The evolving role of statins in the management of atherosclerosis.
J Am Coll Cardiol
2000
35
1
1
10
93
Futterman
LG
Lemberg
L
Statin pleiotropy: fact or fiction?
Am J Crit Care
2004
13
3
244
249
94
Li
H
Lewis
A
Brodsky
S
Rieger
R
Iden
C
Goligorsky
MS
Homocysteine induces 3-hydroxy- 3-methylglutaryl coenzyme A reductase in vascular endothelial cells: a mechanism for development of atherosclerosis?
Circulation
2002
105
9
1037
1043
95
Mühlhäuser
U
Zolk
O
Rau
T
Münzel
F
Wieland
T
Eschenhagen
T
Atorvastatin desensitizes beta-adrenergic signalling in cardiac myocytes via reduced isoprenylation of G-protein gamma-subunits.
FASEB J
2006
20
6
785
787
96
Niemi
M
Schaeffeler
E
Lang
T
et al
High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1).
Pharmacogenetics
2004
14
7
429
440
97
Grube
M
Köck
K
Oswald
S
et al
Organic anion transporting polypeptide 2B1 is a high-affinity transporter for atorvastatin and is expressed in the human heart.
Clin Pharmacol Ther
2006
80
6
607
620
98
Ho
RH
Tirona
RG
Leake
BF
et al
Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics.
Gastroenterology
2006
130
6
1793
1806
99
Bednarek-Tupikowska
G
Gosk
I
Szuba
A
et al
Influence of dehydroepiandrosterone on platelet aggregation, superoxide dismutase activity and serum lipid peroxide concentrations in rabbits with induced hypercholesterolemia.
Med Sci Monit
2000
6
1
40
45
100
Verschoor
A
Neuenhahn
M
Navarini
AA
et al
A platelet-mediated system for shuttling blood-borne bacteria to CD8alpha+ dendritic cells depends on glycoprotein GPIb and complement C3.
Nat Immunol
2011
12
12
1194
1201
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