A complex interaction between Gαi2 and Gαi3

Heterotrimeric G proteins are coupled to seven transmembrane receptors named GPCRs (G protein coupled receptors) to which an extensive array of hormones and chemokines bind, controlling lymphocyte trafficking and differentiation.  Our published and ongoing investigations reveal a complex interaction between Gai2 and Gai3-dependent signaling, which depending on context can be functionally overlapping, distinct, antagonistic, or synergistic in directing lymphocyte migration. 

These findings are of great significance in development of drugs targeting GPCRs.  For instance, FTY720 is an agonist of the sphingosine 1-phosphate (S1P)1 receptor and induces T cell sequestration at the primary and secondary lymphoid tissues, but the underlying mechanism is not fully understood.  Utilizing a novel in vivo flow cytometer, in conjunction with Gαi2- and Gαi3-knockout mice, we demonstrate that FTY720 depends onGαi2 but not Gαi3 in sequestration of T cells in the secondary lymphoid tissues. 

Strikingly, while Gαi2 and Gαi3 are redundant in the S1P1 receptor internalization induced by FTY720, they are antagonistic in regulation of T cell mobility.  FTY720, but not S1P, prefers activation of Gai2 over Gai3, inducing the S1P1 receptor down regulation as well as decreasing T cell motility in lymph nodes.  Preference of activation of Gαi2 over Gαi3 may be the reason that FTY720, but no S1P, can sequester T cells in the secondary lymphoid tissues, although FTY720 and S1P both are agonists for the S1P1 receptor.