Regulation of C3a Receptor Signaling in Human Mast Cells by G Protein Coupled Receptor KinasesReportar como inadecuado

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The complement component C3a activates human mast cells via its cell surface G protein coupled receptor GPCR C3aR. For most GPCRs, agonist-induced receptor phosphorylation leads to receptor desensitization, internalization as well as activation of downstream signaling pathways such as ERK1-2 phosphorylation. Previous studies in transfected COS cells overexpressing G protein coupled receptor kinases GRKs demonstrated that GRK2, GRK3, GRK5 and GRK6 participate in agonist-induced C3aR phosphorylation. However, the roles of these GRKs on the regulation of C3aR signaling and mediator release in human mast cells remain unknown.

Methodology-Principal Findings

We utilized lentivirus short hairpin shRNA to stably knockdown the expression of GRK2, GRK3, GRK5 and GRK6 in human mast cell lines, HMC-1 and LAD2, that endogenously express C3aR. Silencing GRK2 or GRK3 expression caused a more sustained Ca2+ mobilization, attenuated C3aR desensitization, and enhanced degranulation as well as ERK1-2 phosphorylation when compared to shRNA control cells. By contrast, GRK5 or GRK6 knockdown had no effect on C3aR desensitization, but caused a significant decrease in C3a-induced mast cell degranulation. Interestingly, GRK5 or GRK6 knockdown rendered mast cells more responsive to C3a for ERK1-2 phosphorylation.


This study demonstrates that GRK2 and GRK3 are involved in C3aR desensitization. Furthermore, it reveals the novel finding that GRK5 and GRK6 promote C3a-induced mast cell degranulation but inhibit ERK1-2 phosphorylation via C3aR desensitization-independent mechanisms. These findings thus reveal a new level of complexity for C3aR regulation by GRKs in human mast cells.

Autor: Qiang Guo, Hariharan Subramanian, Kshitij Gupta, Hydar Ali



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