Is there a contribution from the N-methyl-D-aspartate receptor to the function of human platelets?

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dc.contributor.advisor Kalev-Zylinska, M en Sun, Peng en 2011-02-26T23:14:14Z en 2010 en
dc.identifier.uri en
dc.description Full text is available to authenticated members of The University of Auckland only. en
dc.description.abstract Glutamate has long been recognised as one of the most important intercellular chemical signals used in the central nervous system (CNS). Neuronal N-methyl-D-aspartate (NMDA) receptors are a group of ionotropic glutamate receptors that are widely expressed in the brain. They are critical for the development of the CNS and subsequent normal neuronal activity, including memory, learning and neuroplasticity. Although NMDA receptors are most known for its expression on neurons, they are also expressed in blood platelets. However, compared to the well-studied neuronal NMDA receptors, the knowledge about their platelet counterparts is limited. The main aim of this study was to characterise NMDA receptor expression in platelets and explore its contribution towards platelet function. Expression of NMDA receptors in human platelets was examined using techniques of Western blotting and platelet enzyme-linked immunosorbent assay (ELISA). Semi-quantitation analysis of Western blot patterns was also performed to relatively compare expression levels of NMDA receptor subunits in platelets versus neurons. Effects of NMDA receptor modulation on platelet function was examined using light transmission aggregometry (LTA) in platelet rich plasma (PRP) in the presence of well-characterised neuronal NMDA receptor antagonists and agonists and a range of platelet modulators: ADP, collagen and epinephrine. Furthermore, previous work done in this laboratory revealed that patients after ischaemic stroke develop antibodies that react with subunit 1 of the NMDA receptors (NR1 protein). Therefore, I also examined in this thesis if anti-NR1 antibodies, both commercial and those derived from stroke patients, bind human platelets and affect platelet aggregation. My results indicate that NMDA receptors are expressed in human platelets. The NR1 protein was found expressed at high levels accompanied by predominantly the NR2D subunit. NMDA receptor antagonists inhibited platelet aggregation, while NMDA receptor agonists showed no inhibition. In contrast, enhancement of aggregation was shown when glycine (NMDA receptor co-agonist) was used in combination with a low dose ADP. My testing of antibodies derived from stroke sera by Western blotting suggested reactivity with the fulllength NR1 protein in neurons and platelets in 13 out of 48 patients. Some of the NR1- positive sera also reacted with intact human platelets, when tested by platelet-ELISA. There was some correlation between the presence of anti-NR1 or anti-platelet antibodies in patients and stroke size and severity. Significantly, anti-NR1 antibodies, including those derived from stroke patients inhibited platelet aggregation. In summary, my work has identified that NMDA receptors are expressed in platelets and contribute to platelet function. Antibodies that target the NR1 component of NMDA receptors develop in patients after stroke and some bind intact human platelets. Significantly, stroke-derived antibodies inhibit platelet function, which may represent a novel physiological mechanism to inhibit thrombosis. Overall, my results suggest a number of novel ways to design new anti-thrombotic drugs through targeting NMDA receptors on platelets, including by anti-NR1 antibodies. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof Masters Thesis - University of Auckland en
dc.relation.isreferencedby UoA99216353914002091 en
dc.rights Restricted Item. Available to authenticated members of The University of Auckland. en
dc.rights.uri en
dc.title Is there a contribution from the N-methyl-D-aspartate receptor to the function of human platelets? en
dc.type Thesis en Biomedical Science en The University of Auckland en Masters en
dc.rights.holder Copyright: the author en
pubs.elements-id 206592 en
pubs.record-created-at-source-date 2011-02-27 en

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