title: Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes.
abstract: CD38 controls the chemotaxis of leukocytes to some, but not all, chemokines, suggesting that chemokine receptor signaling in leukocytes is more diverse than previously appreciated. To determine the basis for this signaling heterogeneity, we examined the chemokine receptors that signal in a CD38-dependent manner and identified a novel "alternative" chemokine receptor signaling pathway. Similar to the "classical" signaling pathway, the alternative chemokine receptor pathway is activated by Galpha(i2)-containing Gi proteins. However, unlike the classical pathway, the alternative pathway is also dependent on the Gq class of G proteins. We show that Galpha(q)-deficient neutrophils and dendritic cells (DCs) make defective calcium and chemotactic responses upon stimulation with N-formyl methionyl leucyl phenylalanine and CC chemokine ligand (CCL) 3 (neutrophils), or upon stimulation with CCL2, CCL19, CCL21, and CXC chemokine ligand (CXCL) 12 (DCs). In contrast, Galpha(q)-deficient T cell responses to CXCL12 and CCL19 remain intact. Thus, the alternative chemokine receptor pathway controls the migration of only a subset of cells. Regardless, the novel alternative chemokine receptor signaling pathway appears to be critically important for the initiation of inflammatory responses, as Galpha(q) is required for the migration of DCs from the skin to draining lymph nodes after fluorescein isothiocyanate sensitization and the emigration of monocytes from the bone marrow into inflamed skin after contact sensitization.
authors.affiliation: Trudeau Institute, Saranac Lake, NY 12983, USA.
authors.forename: Guixiu
authors.initials: G
authors.lastname: Shi
authors.forename: Santiago
authors.initials: S
authors.lastname: Partida-Sánchez
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Misra
authors.forename: Michael
authors.initials: M
authors.lastname: Tighe
authors.forename: Michael T
authors.initials: MT
authors.lastname: Borchers
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Melvin I
authors.initials: MI
authors.lastname: Simon
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lund
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D003713:Dendritic Cells / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D006098:Granulocytes / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019707:Receptors, Chemokine / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D019707:Receptors, Chemokine; D051997:ADP-ribosyl Cyclase 1; D043802:GTP-Binding Protein alpha Subunits, Gq-G11