GRK6 regulates the hemostatic response to injury through its rate-limiting effects on GPCR signaling in platelets

Chen, Xi; Gupta, Shuchi; Cooper, Matthew; DeHelian, Daniel; Zhao, Xuefei; Naik, Meghna U.; Wurtzel, Jeremy G. T.; Stalker, Timothy J.; Goldfinger, Lawrence E.; Benovic, Jeffrey L.; Brass, Lawrence F.; McKenzie, Steven E.; Naik, Ulhas P.; Ma, Peisong

doi:10.1182/bloodadvances.2019000467

Cited by 19 publications

(30 citation statements)

References 42 publications

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“…Using CRISPR-Cas9 genome editing, we generated a GRK6 knockout mouse mutant line. We have shown that loss of GRK6 in mouse platelets increases both PAR4 and P2Y 12 -dependent signaling [25]. Notably, deletion of GRK6 has an effect on mouse PAR4-dependent signaling but not human PAR4-dependent signaling.…”

Section: Regulation Of Thrombin Receptor Signaling By Grk6mentioning

confidence: 85%

“…Messenger RNA and predicted protein copy number analysis in human and mouse platelets have identified the presence of GRK expression [21][22][23]. Further study using immunoblotting has confirmed the expression of specific GRKs (GRK2, GRK5, and GRK6) in platelets [24][25][26]. In human platelets, GRK2, GRK5, and GRK6 are all expressed in the range of 1000-2000 copies per platelet, with GRK6 having the highest expression level.…”

Section: Grks In Plateletsmentioning

confidence: 89%

“…GRK6 regulates the hemostatic response to injury. (A) Increased platelet accumulation in GRK6-/-mice following laser injury in a cremaster muscle arteriole as described by Chen et al [25] Platelets are labeled with fluorescently conjugated anti-CD41 (red), anti-Fibrin (green), and anti-Pselectin (blue). The blue lines mark the vessel walls.…”

Section: Introductionmentioning

confidence: 93%

“…In both human and mouse platelets, GRK6 is the predominant form of GRKs. It impacts platelet activation through targeting of the PARs and P2Y 12 receptors ( Figure 1A) [25]. Human platelets express thrombin receptors, PAR1 and PAR4, but mouse platelets express a PAR3/PAR4 complex [37,38].…”

Section: Role Of Grk6 During Platelet Activationmentioning

confidence: 99%

“…Using human megakaryoblastic cells (MEG-01), it has been shown that there is an increase in Ca 2+ response to PAR1 agonist in GRK6 -/cells, but no change in Ca 2+ response to PAR4 agonist. This suggests that GRK6 regulates PAR1, but not PAR4, receptor-mediated signaling in human platelets [25]. Using CRISPR-Cas9 genome editing, we generated a GRK6 knockout mouse mutant line.…”

Section: Regulation Of Thrombin Receptor Signaling By Grk6mentioning

confidence: 99%

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The Roles of GRKs in Hemostasis and Thrombosis

Chen

Zhao

Cooper

et al. 2020

IJMS

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Along with cancer, cardiovascular and cerebrovascular diseases remain by far the most common causes of death. Heart attacks and strokes are diseases in which platelets play a role, through activation on ruptured plaques and subsequent thrombus formation. Most platelet agonists activate platelets via G protein-coupled receptors (GPCRs), which make these receptors ideal targets for many antiplatelet drugs. However, little is known about the mechanisms that provide feedback regulation on GPCRs to limit platelet activation. Emerging evidence from our group and others strongly suggests that GPCR kinases (GRKs) are critical negative regulators during platelet activation and thrombus formation. In this review, we will summarize recent findings on the role of GRKs in platelet biology and how one specific GRK, GRK6, regulates the hemostatic response to vascular injury. Furthermore, we will discuss the potential role of GRKs in thrombotic disorders, such as thrombotic events in COVID-19 patients. Studies on the function of GRKs during platelet activation and thrombus formation have just recently begun, and a better understanding of the role of GRKs in hemostasis and thrombosis will provide a fruitful avenue for understanding the hemostatic response to injury. It may also lead to new therapeutic options for the treatment of thrombotic and cardiovascular disorders.

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Section: Regulation Of Thrombin Receptor Signaling By Grk6mentioning

confidence: 85%