Neurotransmittors act as platelet activators

The tachykinins comprise a family of peptides, traditionally classified as neurotransmitters, that includes substance P and neurokinins A and B. It is now clear that these peptides mediate a variety of biological functions, including smooth muscle cell contraction, vasodilation, plasma extravasation, neurogenic inflammation, and hematopoiesis. In this issue of Blood, work by Jones and colleagues extends the functional repertoire of tachykinins by revealing an important role in hemostasis and thrombosis.

It now appears that platelets contain substance P and endokinins A and B, which are released upon stimulation and cause positive feedback activation. Platelets circulate in a dormant state, but contact with components in the damaged vessel wall and stimulators generated in plasma start a sequence of reactions resulting in aggregation, secretion of granule contents, and generation of a procoagulant surface. There is a stream of activation signals initiated by receptor stimulation that leads to mobilization of Ca²⁺ ions from internal stores and is facilitated by the GTP-binding protein Gq through signal amplification. Often, this pathway functions far below maximal capacity. The support of 2 feedback mechanisms is essential for rapid execution of platelet aggregation and secretion. One of those mechanisms is the release of ADP, which feeds back to P2Y receptors; the other is the release of thromboxane A₂, which activates thromboxane receptors. The success of clopidogrel and aspirin as antithrombotic medication is based on the interference with P2Y₁₂ signaling and thromboxane A₂ formation, respectively.

The studies by the Gibbins group make it clear that when platelets are stimulated, a third mechanism for feedback stimulation is activated. The secretion reaction liberates substance P and endokinins A and B, which signal through NK-1 receptors on the platelet surface. NK-1 signaling accelerates the Gq-mediated Ca²⁺ mobilization, leading to faster and more extensive aggregation and secretion. The prolongation of the bleeding time and reduction of thromboembolism by deficiencies in NK-1 signaling in an animal model are impressive illustrations of the importance of this feedback loop in hemostasis and thrombosis.

Aspirin and clopidogrel also interfere with tachykinin-induced platelet functions and the result of NK-1 mediated Ca²⁺ mobilization might well be neutralized by these agents at more downstream steps in the NK-1 signaling pathway. However, in addition to Gq-mediated Ca²⁺ increases, the NK-1 receptor might trigger activation mechanisms that escape inhibition by aspirin and clopidogrel. The NK-1 receptor has been reported to couple to other GTP-binding proteins in other cells, causing activation of alternative signaling pathways. Furthermore, receptor-independent modes of action for tachykinins in some cells have been reported.^1,2 

The relevance of alternative signaling pathways in the activation of platelets by tachykinins is uncertain, but the effects of perturbing tachykinin receptors on hemostasis and thrombosis indicate that this new mechanism may be a novel route for the development of antithrombotic treatments.