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Loss of association between activated Gαqand Gβγ disrupts receptor-dependent and receptor-independent signaling

Cellular Signalling
Publication Date
DOI: 10.1016/j.cellsig.2004.12.008
  • Heterotrimeric G Protein
  • Signal Transduction
  • Inositol Phosphate
  • Subcellular Localization
  • Cyclic Amp
  • Biology


Abstract The G protein subunit, βγ, plays an important role in targeting α subunits to the plasma membrane and is essential for binding and activation of the heterotrimer by heptahelical receptors. Mutation of residues in the N-terminal α-helix of α s and α q that contact βγ in the crystal structure of α i reduces binding between α and βγ, inhibits plasma membrane targeting and palmitoylation of the α subunit, and results in G proteins that fail to couple receptor activation to stimulation of effector. Overexpression of βγ can recover this loss of signaling through G s but not G q. In fact, a single mutation (I25A) in α q can block α q-mediated generation of inositol phosphates. Function is not recovered by βγ overexpression nor myristoylation directed plasma membrane localization. Introduction of a Q209L activating mutation with I25A results in a constitutively active α q as expected, but surprisingly a R183C activating mutation does not result in constitutive activity when present with I25A. Examination of binding between α and βγ via a pull down assay shows that the N-terminal βγ-binding mutations inhibit α–βγ binding significantly more than the R183C or Q209L activating mutations do. Moreover, introduction of the I25A mutation into α qRC disrupts co-immunoprecipitation with PLCβ1. Taken together, results presented here suggest that α–βγ binding is necessary at a point downstream from receptor activation of the heterotrimeric G protein for signal transduction by α q.

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