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Molecular Pharmacology

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Centaurin-α1, an ADP-Ribosylation Factor 6 GTPase Activating Protein, Inhibits β2-Adrenoceptor Internalization

Joanna Lawrence, Stuart J. Mundell, Hongruo Yun, Eamonn Kelly and Kanamarlapudi Venkateswarlu
Molecular Pharmacology June 2005, 67 (6) 1822-1828; DOI: https://doi.org/10.1124/mol.105.011338
Joanna Lawrence
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Stuart J. Mundell
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Hongruo Yun
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Eamonn Kelly
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Kanamarlapudi Venkateswarlu
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Abstract

The small GTP-binding protein ADP ribosylation factor 6 (ARF6) has recently been implicated in the internalization of G protein-coupled receptors (GPCRs), although its precise molecular mechanism in this process remains unclear. We have recently identified centaurin α1 as a GTPase activating protein (GAP) for ARF6. In the current study, we characterized the effects of centaurin α1 on the agonist-induced internalization of the β2-adrenoceptor transiently expressed in human embryonic kidney (HEK) 293 cells. Using an enzyme-linked immunosorbent assay as well as confocal imaging of cells, we found that expression of centaurin α1 strongly inhibited the isoproterenol-induced internalization of β2-adrenoceptor. On the other hand, expression of functionally inactive versions of centaurin α1, including an R49C mutant, which has no catalytic activity, and a double pleckstrin homology (PH) mutant (DM; R148C/R273C), which has mutations in both the PH domains of centaurin α1, rendering it unable to translocate to the cell membrane, were unable to inhibit β2-adrenoceptor internalization. In addition, a constitutively active version of ARF6, ARF6Q67L, reversed the ability of centaurin α1 to inhibit β2-adrenoceptor internalization. Finally, expression of centaurin α1 also inhibited the agonist-induced internalization of β2-adrenoceptor endogenously expressed in HEK 293 cells, whereas the R49C and DM mutant versions of centaurin α1 had no effect. Together, these data indicate that by acting as an ARF6 GAP, centaurin α1 is able to switch off ARF6 and so inhibit its ability to mediate β2-adrenoceptor internalization. Thus, ARF6 GAPs, such as centaurin α1, are likely to play a crucial role in GPCR trafficking by modulating the activity of ARF6.

  • Received January 21, 2005.
  • Accepted March 18, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (6)
Molecular Pharmacology
Vol. 67, Issue 6
1 Jun 2005
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Centaurin-α1, an ADP-Ribosylation Factor 6 GTPase Activating Protein, Inhibits β2-Adrenoceptor Internalization

Joanna Lawrence, Stuart J. Mundell, Hongruo Yun, Eamonn Kelly and Kanamarlapudi Venkateswarlu
Molecular Pharmacology June 1, 2005, 67 (6) 1822-1828; DOI: https://doi.org/10.1124/mol.105.011338

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Centaurin-α1, an ADP-Ribosylation Factor 6 GTPase Activating Protein, Inhibits β2-Adrenoceptor Internalization

Joanna Lawrence, Stuart J. Mundell, Hongruo Yun, Eamonn Kelly and Kanamarlapudi Venkateswarlu
Molecular Pharmacology June 1, 2005, 67 (6) 1822-1828; DOI: https://doi.org/10.1124/mol.105.011338
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