A chemoattractant-mediated Gi-coupled pathway activates adenylyl cyclase in human neutrophils

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 mech...

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Bibliographic Details
Published in:Molecular biology of the cell 2007-02, Vol.18 (2), p.512-522
Main Authors: Mahadeo, Dana C, Janka-Junttila, Mirkka, Smoot, Rory L, Roselova, Pavla, Parent, Carole A
Format: Article
Language:English
Subjects:
Adenylyl Cyclases - analysis
Adenylyl Cyclases - metabolism
Animals
Chemotactic Factors - pharmacology
Chemotaxis, Leukocyte
Colforsin - pharmacology
Cytoskeleton - physiology
Dictyostelium - enzymology
Dictyostelium - physiology
Enzyme Activation
GTP-Binding Protein alpha Subunits, Gi-Go - metabolism
Humans
Neutrophils - drug effects
Neutrophils - enzymology
Neutrophils - immunology
Pertussis Toxin - pharmacology
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
Signal Transduction - drug effects
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Summary: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 Galpha(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 Galpha(s)-meditated pathway.
ISSN:1059-1524
DOI:10.1091/mbc.E06-05-0418