TABLE 1

GPCRs that have been shown to undergo arrestin-independent agonist-induced or constitutive endocytosis

ReceptorMechanism of internalizationCell lineMethod used to show arrestin independenceReference
Arrestin-independent agonist-induced endocytosis
β1- and α2a-adrenoceptors and D4FEMEBS-C-1Indirect evidence (FEME is clathrin- and arrestin-independent)Boucrot et al., 2015
β2-adrenoceptor and AT1ACaveolae (partial arrestin-dependence)HEK293, COS-7Dominant negative arrestin (arrestin-2-V53D)Guo et al., 2015
5-HT2ADynamin-dependentHEK293, C6Dominant negative arrestins (arrestin-2-V53D, arrestin-2319−418, arrestin-3284−409)Bhatnagar et al., 2001; Gray et al., 2001
ApelinClathrin-dependentHEK293Dominant negative arrestin (arrestin-2319−418)Pope et al., 2016
BLT1Dynamin- and GRK2 phosphorylation-dependentRBL-2H3Dominant negative arrestin (arrestin-2-V53D)Chen et al., 2004b
D3Clathrin- and dynamin-dependent, FEMECHO, HEK293, BS-C-1Dominant negative arrestins (arrestin-2-V53D, arrestin-3-V54D)Boucrot et al., 2015; Xu et al., 2019
ETACaveolae (partial arrestin-dependence)HEK293Arrestin-AP-2 BRET, arrestin-AP-2 complex inhibitor (barbadin), arrestin-2/3 siRNAOkamoto et al., 2000; Hamdan et al., 2007; Beautrait et al., 2017
ETBUnknown (partial arrestin-dependence)HEK293Arrestin-AP-2 BRET, arrestin-2/3 siRNAHamdan et al., 2007
FPR1GRK phosphorylation-dependentMEFs, U937Arrestin-2/3−/− MEFs, dominant negative arrestin (arrestin-2319−418)Hsu et al., 1997; Gilbert et al., 2001; Vines et al., 2003
GLP-1Dynamin-dependent and caveolaeHEK293, MIN6HEK293-Δarrestin-2/3, arrestin-3 overexpressionSyme et al., 2006; Jones et al., 2018
GLP-2CaveolaeBHK-21, DLD-1Indirect evidence (dynamin-independent and C-terminal truncated receptor mutant)Estall et al., 2004, 2005
IPClathrin- and dynamin-dependentHEK293Dominant negative arrestin (arrestin-2319−418)Smyth et al., 2000
M1Clathrin- and dynamin-dependenttsA201, MDCK, HEK293Overexpression of arrestin-2 and -3, dominant negative arrestin (arrestin-2319−418)Lee et al., 1998; Vögler et al., 1998; Shmuel et al., 2007
M2Phosphorylation- and Arf6 GTPase–dependenttsA201, HeLaArrestin-2 and -3 overexpressionPals-Rylaarsdam et al., 1997; Delaney et al., 2002
M3Dynamin-dependenttsA201, HEK293Overexpression of arrestin-2 and -3, dominant negative arrestin (arrestin-2319−418)Lee et al., 1998; Vögler et al., 1998
M4Dynamin-dependent, FEMEtsA201, BS-C-1Overexpression of arrestin-2 and -3, dominant negative arrestin (arrestin-2319−418)Lee et al., 1998; Vögler et al., 1998; Boucrot et al., 2015
PAR1Dependent on clathrin, dynamin, phosphorylation, epsin-1 and AP-2MEFs, COS-7, HeLa, HEK293Arrestin-2/3−/− MEFsPaing et al., 2002; Paing et al., 2006; Chen et al., 2011
PAR4Dependent on clathrin, AP-2 and dynaminHeLaArrestin-2/3−/− MEFsSmith et al., 2016
PKR2GRK2 phosphorylation- and clathrin-dependentHEK293Dominant negative arrestins (arrestin-2-V53D, arrestin-3-V54D), arrestin-2 and -3 siRNAYin et al., 2014
SecretinPKA-dependentHEK293Dominant negative arrestin (arrestin-2-V53D)Walker et al., 1999
UTUnknownHEK293, MEFsDominant negative arrestin (arrestin-3-V54D), arrestin-2/3−/− MEFsGiebing et al., 2005
Constitutive internalization
CaSUnknown (partial arrestin-dependence)HEK293HEK293-Δarrestin-2/3Mos et al., 2019
CXCR4Dynamin- and PKC-dependentHEK293 COS-7Indirect evidence (C-terminal truncated mutant)Signoret et al., 1997, 1998
ADGRA3Clathrin-dependentHEK293HEK293-Δarrestin-2/3Spiess et al., 2019
M3 and β2-adrenoceptorMHC-IHeLa, COS-7Indirect evidence (clathrin-independent)Scarselli and Donaldson, 2009
mGlu5Dynamin-dependent, caveolaeCOS-7Indirect evidence (clathrin-independent)Fourgeaud et al., 2003
mGlu7MHC-IHeLaIndirect evidence (clathrin-independent)Lavezzari and Roche, 2007
PAR1Clathrin- and AP-2-dependentMEFs, COS-7, HeLa, HEK293Arrestin-2/3−/− MEFsPaing et al., 2002, 2006
TPβClathrin- and dynamin-dependentHEK293, CHODominant negative arrestin (arrestin-3201−409)Parent et al., 2001
US28Clathrin-dependentHeLa, MEFsArrestin-2/3−/− MEFsFraile-Ramos et al., 2003
XCR1UnknownHEK293HEK293-Δarrestin-2/3Bauer et al., 2019
  • Arf6, ADP-ribosylation factor 6; BHK-21, baby hamster kidney fibroblasts; MDCK; Madin-Darby canine kidney; PKA, protein kinase A.