A β-Arrestin Binding Determinant Common to the Second Intracellular Loops of Rhodopsin Family G Protein-coupled Receptors*

By S. Marion, R. Oakley, Kyeong-Man Kim, M. Caron, L. Barak. Journal of Biological Chemistry, 2006

100 citations recorded by the source corpus.

β-Arrestins have been shown to inhibit competitively G proteindependent signaling and to mediate endocytosis for many of the hundreds of nonvisual rhodopsin family G protein-coupled receptors (GPCR). An open question of fundamental importance concerning the regulation of signal transduction of several hundred rhodopsin-like GPCRs is how these receptors of limited sequence homology, when considered in toto, can all recruit and activate the two highly conserved β-arrestin proteins as part of their signaling/desensitization process. Although the serine and threonine residues that form GPCR kinase phosphorylation sites are common β-arrestin-associated receptor determinants regulating receptor desensitization and internalization, the agonist-activated conformation of a GPCR probably reveals the most fundamental determinant mediating the GPCR and arrestin interaction. Here we identified a β-arrestin binding determinant common to the rhodopsin family GPCRs formed from the proximal 10 residues of the second intracellular loop. We demonstrated by both gain and loss of function studies for the serotonin 2C, β2-adrenergic, α2a-adrenergic, and neuropeptide Y type 2 receptorsthat the highly conserved amino acids, proline and alanine, naturally occurring in rhodopsin family receptors six residues distal to the highly conserved second loop DRY motif regulate β-arrestin binding and β-arrestin-mediated internalization. In particular, as demonstrated for the β2 AR, this occurs independently of changes in GPCR kinase phosphorylation. These results suggest that a GPCR conformation directed by the second intracellular loop, likely using the loop itself as a binding patch, may function as a switch for transitioning β-arrestin from its inactive form to its active receptor-binding state.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1a1f9ac11121fa796dd388737fc434977f3f4947

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In Cellular and Molecular Neuroscience

  1. R. J. Lefkowitz
  2. Seungkirl Ahn
  3. S. Rajagopal
  4. A. Shukla

In Molecular Biology

  1. R. J. Lefkowitz
  2. Seungkirl Ahn
  3. S. Rajagopal
  4. A. Shukla
  5. Kunhong Xiao
  6. Terrence G. Oas
  7. Éric Reiter
  8. Sudha K. Shenoy

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