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Vol. 18, Issue 2, 512-522, February 2007

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A Chemoattractant-mediated G_i-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256

Submitted May 16, 2006; Revised November 15, 2006; Accepted November 21, 2006
Monitoring Editor: John York

Neutrophils and Dictyostelium use conserved signal transduction pathways to decipher chemoattractant gradients and migrate directionally. In both cell types, addition of chemoattractants stimulates the production of cAMP, which has been suggested to regulate chemotaxis. We set out to define the mechanism by which chemoattractants increase cAMP levels in human neutrophils. We show that chemoattractants elicit a rapid and transient activation of adenylyl cyclase (AC). This activation is sensitive to pertussis toxin treatment but independent of phosphoinositide-3 kinase activity and an intact cytoskeleton. Remarkably, and in sharp contrast to G_s-mediated activation, chemoattractant-induced AC activation is lost in cell lysates. Of the nine, differentially regulated transmembrane AC isoforms in the human genome, we find that isoforms III, IV, VII, and IX are expressed in human neutrophils. We conclude that the signal transduction cascade used by chemoattractants to activate AC is conserved in Dictyostelium and human neutrophils and is markedly different from the canonical G_s-meditated pathway.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Carole A. Parent (parentc{at}helix.nih.gov)

Abbreviations used: AC, adenylyl cyclase; C5a, complement factor 5a; fMLP, N-formylmethionyl-leucyl-phenylalanine; GTPS, guanosine 5'-O-(3-thio)triphosphate; LTB₄, leukotriene B4; PTX, pertussis toxin.

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