Constitutive activation and endocytosis of the complement factor 5a receptor: Evidence for multiple activated conformations of a G protein-coupled receptor

Jennifer Whistler, Basil O. Gerber, Elaine C. Meng, Thomas J. Baranski, Mark von Zastrow, Henry R. Bourne

Research output: Contribution to journalReview article

46 Scopus citations


Serpentine receptors relay hormonal or sensory stimuli to heterotrimeric guanine nucleotide-binding proteins (G proteins). In most G protein-coupled receptors (GPCRs), binding of the agonist ligand elicits both stimulation of the G protein and endocytosis of the receptor. We have begun to address whether these responses reflect the same sets of conformational changes in the receptor using constitutively active mutants of the human complement factor 5a receptor (C5aR). Two different mutant receptors both constitutively activate G protein-mediated responses, but one (F251A) is endocytosed only in response to ligand stimulation, while the other (NQ) is constitutively internalized in the absence of ligand. Both the constitutive and ligand-dependent endocytosis are accompanied by recruitment of beta-arrestin to the receptor. An inactivating mutation (N296A) complements the NQ mutation, producing a receptor that is activated only upon exposure to agonist; this revertant receptor (NQ/N296A) is nevertheless constitutively endocytosed. Thus one mutant (F251A) requires agonist for triggering endocytosis but not for activation of the downstream G protein signal, while another (NQ/N296A) behaves in the opposite fashion. Dissociation of two responses normally dependent on agonist binding indicates that the corresponding functions of an activated GPCR reflect difterent sets of changes in the receptor's conformation.

Original languageEnglish (US)
Pages (from-to)866-877
Number of pages12
Issue number12
StatePublished - Dec 1 2002
Externally publishedYes



  • Arrestin
  • C5a
  • Constitutive activation
  • Endocytosis

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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