Caveolin-1 regulates cellular trafficking and function of the glucagon-like Peptide 1 receptor

Mol Endocrinol. 2006 Dec;20(12):3400-11. doi: 10.1210/me.2006-0178. Epub 2006 Aug 24.


The glucagon-like peptide 1 receptor (GLP-1R) mediates important effects on beta-cell function and glucose homeostasis and is one of the most promising therapeutic targets for type 2, and possibly type 1, diabetes. Yet, little is known regarding the molecular and cellular mechanisms that regulate its function. Therefore, we examined the cellular trafficking of the GLP-1R and the relation between receptor localization and signaling activity. In resting human embryonic kidney 293 and insulinoma MIN6 cells, a fully functional green fluorescent protein-tagged GLP-1R was localized both at the cell membrane and in highly mobile intracellular compartments. Real-time confocal fluorescence microscopy allowed direct visualization of constitutive cycling of the receptor. Overexpression of K44A-dynamin increased the number of functional receptors at the cell membrane. Immunoprecipitation, sucrose sedimentation, and microscopy observations demonstrated that the GLP-1R localizes in lipid rafts and interacts with caveolin-1. This interaction is necessary for membrane localization of the GLP-1R, because overexpression of a dominant-negative form of caveolin-1 (P132L-cav1) or specific mutations within the putative GLP-1R's caveolin-1 binding domain completely inhibited GLP-1 binding and activity. Upon agonist stimulation, the GLP-1R underwent rapid and extensive endocytosis independently from arrestins but in association with caveolin-1. Finally, GLP-1R-stimulated activation of ERK1/2, which involves transactivation of epidermal growth factor receptors, required lipid raft integrity. In summary, the interaction of the GLP-1R with caveolin-1 regulates subcellular localization, trafficking, and signaling activity. This study provides further evidence of the key role of accessory proteins in specifying the cellular behavior of G protein-coupled receptors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism*
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism*
  • Cells, Cultured
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Membrane Microdomains / chemistry
  • Membrane Microdomains / metabolism
  • Membrane Microdomains / ultrastructure
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mutation
  • Protein Transport
  • Receptors, Glucagon / analysis
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism*


  • Caveolin 1
  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Receptors, Glucagon
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3