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The stop clock of platelet activation

Simon C. Pitchford

In this issue of Blood, Ma et al provide a novel explanation as to how regulators of G protein signaling proteins (RGSs) can be coordinated by both platelet agonists (eg, thrombin) or platelet inhibitors (eg, prostacyclin) to dampen persistent platelet activation that does not then become physiologically inappropriate.1 There are ≥37 genes encoding RGS proteins in the human genome, and, in the context of hematology, RGS proteins have been described to control hematopoietic cell function (adhesion, migration, and granule release), a role during megakaryopoiesis (differentiation and platelet formation), and the control of platelet function.2 Human platelets contain messenger RNA for at least RGS1, 2, 3, 6, 9, 10, 16, 18, and 19, with RGS10 and RGS18 being predominant. Thus far, the roles of RGS proteins in platelet function are poorly understood.3

A model for modulating platelet reactivity through regulated control of RGS proteins. Platelets can achieve free RGS18 levels by ≥3 states: resting (inactive), after activation by agonist (active; thrombin stimulation), and resistance to activation (active; PGI2-mediated suppression). AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; GTP, guanosine triphosphate; IP, prostacyclin; PIP, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PLC, phospholipase C; SFK, Src family kinases; TxA2, thromboxane A2. See Figure 7 in the article by Ma et al that begins on page 2611.

As potent negative modulators of G protein coupling receptor (GPCR) signaling, RGS proteins bind to activated G protein α subunits (Gα) and accelerate the activity of GTPase, thus enhancing G protein deactivation via hydrolysis of Gα-bound GTP, allowing Gα to reform with Gβγ. The functional relevance of RGS10 and RGS18 proteins in platelet physiology is known, where they have been reported to bind to a phosphorylated scaffold protein spinophilin (SPL) and the Src-homology region 2 domain-containing phosphatase-1 (SHP-1).4 Thrombin activates SHP-1 leading to dephosphorylation of SPL and the release of RGS10 and RGS18.4 In another study, the interaction of platelet RGS18 with 14-3-3γ binding protein occurs in resting platelets and paradoxically increased when platelets become activated.5

It is in this context that Ma et al attempt to rationalize this apparent contradiction of free and bound RGS18 and have investigated how RGS proteins could be applied to act as a brake to platelet activation, but only when needed, thus acting in a dynamic and temporal manner to allow physiological function to occur in the first instance. They show that in resting platelets, free RGS18 levels are low, but increase on thrombin activation; contrarily, free RGS18 levels also rise when platelets are rendered resistant to activation by prostaglandin I2 (PGI2), which increases platelet cAMP. The mechanisms that raise free RGS18 and thus how RGS18 loses bound SHP-1, SPL, or 14-3-3γ are different after activation by agonist (thrombin) compared with active suppression by inhibitor PGI2, or resting states, which is neatly summarized in the cartoon drawn by the authors of the present paper and reproduced here (see figure).1

Immediate questions that arise from this work are what is the role of the other predominant platelet RGS protein (RGS10)? Furthermore, there is a need to better understand the specific roles of the 14-3-3γ/RGS18 complex, as well as the SPL/RGS18/SHP-1 complex in modulating RGS18 activity. These interactions may be significantly dynamic on a temporal basis and so the interactions of these opposing complexes would make interesting study. The dependency of these complexes on the concentration of the primary agonist or, indeed specific agonists, is not known.

Further afield, RGS proteins have been described to control the actions of neutrophils, lymphocytes, and monocytes in functions that are pertinent to host defense.6,7 Given the extraordinary advances being made currently uncovering the contribution of platelets also to host defense, inflammatory diseases, and cancer metastasis, it might be myopic to restrict the evaluation of RGS proteins on platelet function solely to hemostasis, because the activation of platelets during hemostasis is likely to be fundamentally different to the activation of platelets during host defense and inflammation, yet our knowledge of this is in its infancy.8,9

It is apparent that small molecule inhibitors of RGS proteins have been synthesized to demonstrate that these proteins are a “druggable” target elsewhere in the body.10 Such tools might also be developed to investigate novel approaches to controlling the stop clock of platelet activation during hemostasis or host defense. Thus, the mechanisms by which RGS proteins modulate platelet reactivity should be of interest to the clinicians.

Footnotes

  • Conflict-of-interest disclosure: The author declares no competing financial interests.

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