title: G alpha 16 couples chemoattractant receptors to NF-kappa B activation.
abstract: The guanine nucleotide-binding regulatory protein alpha-subunit, Galpha(16), is primarily expressed in hemopoietic cells, and interacts with a large number of seven-membrane span receptors including chemoattractant receptors. We investigated the biological functions resulting from Galpha(16) coupling of chemoattractant receptors in a transfected cell model system. HeLa cells expressing a kappaB-driven luciferase reporter, Galpha(16), and the formyl peptide receptor responded to fMLP with a approximately 7- to 10-fold increase in luciferase activity. This response was accompanied by phosphorylation of IkappaBalpha and elevation of nuclear kappaB-DNA binding activity, indicating activation of NF-kappaB. In contrast to Galpha(16), expression of Galpha(q), Galpha(13), and Galpha(i2) resulted in a marginal increase in kappaB luciferase activity. A GTPase-deficient, constitutively active Galpha(16) mutant (Q212L) could replace agonist stimulation for activation of NF-kappaB. Furthermore, expression of Galpha(16) (Q212L) markedly enhanced TNF-alpha-induced kappaB reporter activity. The Galpha(16)-mediated NF-kappaB activation was paralleled by an increase in phospholipase C-beta activity, and was blocked by pharmacological inhibitors of protein kinase C (PKC) and by buffering of intracellular Ca(2+). The involvement of a conventional PKC isoform was confirmed by the finding that expression of PKCalpha enhanced the effect of Galpha(16), and a dominant negative PKCalpha partially blocked Galpha(16)-mediated NF-kappaB activation. In addition to formyl peptide receptor, Galpha(16) also enhanced NF-kappaB activation by the C5a and C3a receptors, and by CXC chemokine receptor 2 and CCR8. These results suggest a potential role of Galpha(16) in transcriptional regulation downstream of chemoattractant receptors.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Illinois, 8356 South Walcott Avenue, Chicago, IL 60612, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.forename: H
authors.initials: H
authors.lastname: Sang
authors.forename: A
authors.initials: A
authors.lastname: Rahman
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.forename: A B
authors.initials: AB
authors.lastname: Malik
authors.forename: R D
authors.initials: RD
authors.lastname: Ye
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D017930:Genes, Reporter; D005973:Glutamine / Q000235:genetics; D006367:HeLa Cells; D020962:Heterotrimeric GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D007930:Leucine / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D054799:Phospholipase C beta; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics; D018000:Receptors, Peptide / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014162:Transfection / Q000379:methods; D010738:Type C Phospholipases / Q000378:metabolism / Q000502:physiology
chemical_list: D007527:Isoenzymes; D016328:NF-kappa B; D019707:Receptors, Chemokine; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D018000:Receptors, Peptide; D015534:Trans-Activators; D005973:Glutamine; D008156:Luciferases; D010738:Type C Phospholipases; D054799:Phospholipase C beta; C112631:G protein alpha 16; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D007930:Leucine