An Essential Role for RGS Protein/Gαi2 Interactions in B Lymphocyte–Directed Cell Migration and Trafficking

Abstract

Chemokines engage B lymphocyte surface receptors, triggering heterotrimeric G protein Gαi subunit guanine nucleotide exchange. RGS proteins limit the duration that Gαi subunits remain GTP bound, and the loss of an individual RGS protein typically enhances chemokine receptor signaling. In this study, we show that B cells carrying a Gαi2G184S/G184S mutation that disables all RGS protein/Gαi2 interactions exhibit an unexpectedly severe reduction in chemokine receptor signaling. The Gαi2G184S/G184S B cells have markedly elevated basal calcium levels, but poor chemokine-induced increases, enhanced nonspecific migration, but extremely poor chemotaxis. In striking contrast, the Gαi2G184S/G184S B cells exhibited enhanced sensitivity to sphingosine 1-phosphate (S1P). S1P elicited heightened intracellular calcium responses and enhanced S1P-triggered cell migration. Mice with the Gαi2G184S/G184S mutation displayed excessive numbers of germinal center–like structures; abnormal serum Ig profiles; and aberrant B lymphocyte trafficking. These findings establish an essential role for RGS proteins in B cell chemoattractant signaling and for the proper position of B lymphocytes in lymphoid organs.