Peripheral tachykinins and the neurokinin receptor NK1 are required for platelet thrombus formation

Abstract

Platelets play an important role in hemostasis, with inappropriate platelet activation being a major contributor to debilitating and often fatal thrombosis by causing myocardial infarction and stroke. Although current antithrombotic treatment is generally well tolerated and effective, many patients still experience cardiovascular problems, which may reflect the existence of alternative underlying regulatory mechanisms in platelets to those targeted by existing drugs. In this study, we define a role for peripherally distributed members of the tachykinin family of peptides, namely substance P and the newly discovered endokinins A and B that are present in platelets, in the activation of platelet function and thrombus formation. We have reported previously that the preferred pharmacologically characterized receptor for these peptides, the NK1 receptor, is present on platelets. Inhibition or deficiency of the NK1 receptor, or SP agonist activity, resulted in substantially reduced thrombus formation in vitro under arterial flow conditions, increased bleeding time in mice, and a decrease in experimentally induced thromboembolism. Inhibition of the NK1 receptor may therefore provide benefit in patients vulnerable to thrombosis and may offer an alternative therapeutic target.

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“…Hemokinin 1 is presumed to be more resistant to proteolysis than Substance P [184]. Endokinins and hemokinins are not regarded to be conserved throughout mammalian species in contrast to the other tachikinins mentioned above [54] [185]. Tachikinins are identified in neuronal but also in non-neuronal cells like endothelium and inflammatory cells [190]- [192].…”

“…Substance P (RPKPQQFFGLM) contains 11 a.a.r [181] [186]. The amino acid sequences of the further petides are for NKA:HKTDSFVGLM; NKB:DMHDFFVGLM and NKG, which is the most abundant in the body: DAGHGQISHKRHKTDSFVGLM, NP K: DADSSIEKQVALLKALYGHGQISH-KRHKTDSFVGLM; EKA/B: GKASQFFGLM [185]; EKC, EKD: KKAYQLEHTFQGLL, and VGAYQLEHT-FQGLL [187] and hHK1: TGKASQFFGLM [188]. The first five of these tachykinins occur by cleaving of 4 precursor pro-peptides.…”

“…The family of tachykinins includes in humans ten compounds of which eight share the carboxy terminal sequence F-X-G-L-M (X stands either for an aromatic amino acid or a ß-aliphatic amino acid) [178]- [180]: substance P (SP), neurokinin A (NK-A also called substance K), neurokinin B (NK-B also called neuromedin K) [181], neuropeptide K (NP-K), neuropeptide γ (NPG) [181]- [183] and human hemokinin-1 [184] belonging like EKA, B, C and EKD to the group of endokinins [179] [185]. The number of a. a.rs of these tachykinins has been found to be between 10 -36.…”

“…Three types of tachikinin receptors have been identified up to now: TACR1 (NK1), TACR2 (NK2) and TaCR3 (NK3) [8] which may influence a myriad of cell biological effects including diverse actions on cell proliferation, smooth muscle contraction, vasodilation, plasma extravasation, neurogenic inflammation and hematopoiesis [185] [195]. Neurokinin receptors influence via G q/11 -protein phospholipase C and Ca 2+ levels [17].…”

“…These precursor pro-tachykinins, α, β, γ and δ are encoded by two genes. PPT-B gene (alternatively PPT-II or TAC3) encodes the NK-B and PPT-A gene (alternatively PPT-I or TAC1) the other four mammalian tachykinins [185] [189]. Hemokinins as well as endokinins (A-D) are encoded by the TAC4 gene (alternatively PPT-C gene).…”