title: 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 Gαi2 (G184S/G184S) mutation that disables all RGS protein/Gαi2 interactions exhibit an unexpectedly severe reduction in chemokine receptor signaling. The Gαi2 (G184S/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 Gαi2 (G184S/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 Gαi2 (G184S/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.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Il-Young
authors.initials: IY
authors.lastname: Hwang
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Chung
authors.initials: C
authors.lastname: Park
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Harrison
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, 31432 Toulouse Cedex 4, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Boularan
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, 31432 Toulouse Cedex 4, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Galés
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and jkehrl@niaid.nih.gov.
authors.forename: John H
authors.initials: JH
authors.lastname: Kehrl
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D061251:Primary Cell Culture; D011485:Protein Binding; D020710:RGS Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D018925:Chemokines; D008246:Lysophospholipids; D020710:RGS Proteins; C060506:sphingosine 1-phosphate; D051960:GTP-Binding Protein alpha Subunit, Gi2; C498016:Gnai2 protein, mouse; D013110:Sphingosine; D002118:Calcium