NMDA Receptors Play an Anti-aggregating Role in Human Platelets

Abstract

SummaryReceptors for different monoamines, peptides and other neurohormones are present in the plasma membrane of platelets, and the sophisticated process of haemostasis is regulated by the interplay of their physiologic agonists (1). The recent report of a platelet binding* site for phencyclidine (2) suggested a possible role of N-methyl-D-aspartate (NMDA) receptors in platelet function. Isotherms of [3H]-glutamate (GLU), [3H]-CGP-39653, [3H]-glycine (GLY) and [3H]-MK-801 carried out in platelet membranes yielded Bmax and Kd values for these ligands similar to those present in neurons, and NMDA only partially displaced [3H]-GLU. In neurons [3H]-MK-801 binding is potentiated by GLU and/or GLY and, being specific for the open NMDA receptor channel species, it has a functional meaning. In platelet membranes neither GLU and/or GLY increased [3H]-MK-801 binding; thus suggesting that NMDA receptors in platelets are different from those present in neurons. GLU or NMDA alone did not induce platelet aggregation. However, both amino acids were antagonistic on the aggregating activity of arachidonic acid (AA), NMDA being 3 orders of magnitude more active than GLU, and NMDA also antagonized adenosine diphosphate (ADP) and platelet aggregating factor (PAF) induced platelet aggregation. Finally, NMDA increased cAMP levels in intact platelets, and such an effect did not occur in a Ca2+-free medium; yet, cAMP increase was not antagonized by the calmodulin inhibitor trifluoperazine (TFP). It was concluded that platelet membranes carry an NMDA receptor, functionally distinct from the neuronal one, which seems to play an anti-aggregating role.

Increased Plasma Glutamate in Stroke Patients Might Be Linked to Altered Platelet Release and Uptake

“…Although the biological meaning of this process is still unclear, it could be linked to the regulation of platelet activation and aggregation itself. As a matter of fact, platelets have been shown to possess NMDA receptors, which may play an antiaggregating role on activation (Franconi et al, 1996). Additionally, glutamate might be involved in modulating the functions of white blood cells (Kuo et al, 2001), possibly playing a role in the interaction between platelets and leukocytes at the level of the tissue injury.…”

“…Interestingly, a putative role for glutamate in modulating the functions of blood cells has already been proposed. In fact, platelets (Franconi et al, 1996), white blood cells (Kuo et al, 2001), and endothelial cells (Sharp et al, 2003) express functional NMDA receptors, suggesting that they are possible peripheral targets for glutamate released into the circulation.…”

NMDA receptor–mediated regulation of human megakaryocytopoiesis

“…Franconi et al suggested that these receptors were not identical to those identified in the CNS. 29 However NMDA and glutamate antagonized the aggregating activity of arachidonic acid (AA) and NMDA inhibited adenosine diphosphate (ADP) and platelet activating factor (PAF)-induced platelet aggregation. In addition NMDA increased intracellularfree calcium concentrations in platelets and completely inhibited synthesis of thromboxane B-2, an aggregation-promoting agent, from AA.…”

Glutamate transporters in platelets: EAAT1 decrease in aging and in Alzheimer’s disease

“…Platelets were extensively studied as models of synaptic apparatus, since they release and reuptake neurotransmitters such as serotonin and dopamine [3,57], express serotonin [51] and glutamate receptors [23,50] and they served as clinical markers for neuropsychiatric disorders such as depression. Moreover, in AD they were recently proposed as CNS model to study molecular amyloid-precursor protein (APP) alterations [9].…”