The Journal of Experimental Medicine
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Published online October 15, 2007
doi:10.1084/jem.20071267
The Journal of Experimental Medicine, Vol. 204, No. 11, 2705-2718
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Shi et al.
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ARTICLE

 Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes

Guixiu Shi1, Santiago Partida-Sánchez1, Ravi S. Misra1, Michael Tighe1, Michael T. Borchers2, James J. Lee3, Melvin I. Simon4, and Frances E. Lund1

1 Trudeau Institute, Saranac Lake, NY 12983
2 Department of Internal Medicine, Pulmonary Division, University of Cincinnati College of Medicine, Cincinnati, OH 45219
3 Division of Hematology/Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ 85259
4 Division of Biology, California Institute of Technology, Pasadena, CA 91125

CORRESPONDENCE Frances E. Lund: flund{at}trudeauinstitute.org

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 G{alpha}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 G{alpha}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, G{alpha}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 G{alpha}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.

Abbreviations used: 2-APB, 2-aminoethoxydiphenylborate; ADPR, adenosine diphosphoribose; cADPR, cyclic ADPR; CCL and CCR, CC chemokine ligand and receptor, respectively; CI, chemotactic index; CXCL and CXCR, CXC chemokine ligand and receptor, respectively; DNFB, dinitrofluorobenzene; fMLF, N-formyl methionyl leucyl phenylalanine; IP3, inositol trisphosphate; LC, Langerhans cell; mFPR, mouse formyl peptide receptor; NAD+, nicotinamide adenine dinucleotide; PAF, platelet-activating factor; PLC, phospholipase; PTx, pertussis toxin.

G. Shi and S. Partida-Sánchez contributed equally to this work.

S. Partida-Sánchez's present address is Dept. of Pediatrics, Columbus Children's Research Institute, Columbus, OH 43205.


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