TABLE 1

Ubiquitinated GPCRs

A search of the literature for all known ubiquitinated mammalian class A, B, and C GPCRs was performed. This list includes the GPCR family name, the IUPHAR-designated nomenclature, the nature of GPCR ubiquitination, including constitutive or agonist-activated, the ubiquitin E3 ligases and deubiquitinating enzymes, the reported function and references.

Receptor Family and IUPHAR Name	Ubiquitination	E3 Ligase	DUB	Function	References
Class A
Adenosine receptors
A_2A	Constitutive	N.D.	USP4	Deubiquitination required for surface expression	Milojevic et al., 2006
Adrenoceptors
β2	Agonist-induced	Nedd4–1	USP20, USP33	Lysosomal degradation, regulation of arrestin-mediated signaling	Berthouze et al., 2009; Shenoy et al., 2009, 2008
Angiotensin receptors
AT₁	Via D₅R Activation	N.D.	N.D.	Proteosomal degradation	Li et al., 2008
Chemokine receptors
CXCR4	Agonist-induced	AIP4	USP14	Lysosomal degradation	Marchese and Benovic, 2001; Marchese et al., 2003; Mines et al., 2009
CXCR7	Constitutive	N.D.	N.D.	Ubiquitination required for surface expression	Canals et al., 2012
Dopamine receptors
D₁, D₂	Constitutive	N.D.	N.D.		Rondou et al., 2008
D₄	Constitutive	Roc1-Cul3-KLHL12 complex	N.D.	Not required for degradation, K48-linked ubiquitination	Rondou et al., 2008, 2010
D₅	Constitutive, Agonist-induced	N.D.	N.D.	Directs AT₁R degradation	Li et al., 2008; Rondou et al., 2008
Glycoprotein hormone receptors
FSH receptor	Constitutive	N.D.	N.D.	ICL-3 ubiquitination regulates surface expression	Cohen et al., 2003
Lysophospholipid receptors
LPA₂	Agonist-induced	N.D.	N.D.	Promotes cell survival via codegradation of Siva-1	Lin et al., 2007
S₁P	Induced by inhibitor FTY720	WWP2	N.D.	Promotes pulmonary vascular leakage	Oo et al., 2007, 2011
Melanocortin receptors
MCR₂	Agonist-induced	Mahogunin	N.D.	Multi-monoubiquitination	Cooray et al., 2011
Opioid receptors
μ	Agonist-induced	N.D.	N.D.	Agonist-specific ubiquitination, codegradation with δ	Groer et al., 2011; He et al., 2011; Henry et al., 2011
δ	Agonist-induced	AIP4	N.D.	Non-ubiquitin-mediated degradation, codegradation with μ	Tanowitz and Von Zastrow, 2002; Hislop et al., 2009; He et al., 2011; Henry et al., 2011
κ	Constitutive, enhanced by agonist	N.D.	N.D.	K63-linked ubiquitination	Li et al., 2008
Orexin receptors
OX₂	Via TNF-α Stimulation	N.D.	N.D.	TNF-α stimulation causes degradation	Zhan et al., 2011
Platelet-activating receptor
PAF receptor	Constitutive	N.D.	N.D.	Proteosomal and lysosomal degradation	Dupré et al., 2003
Prostanoid receptors
IP₁	Agonist-induced	N.D.	N.D.	Lysosomal degradation	Donnellan and Kinsella, 2009
Protease-activated receptors
PAR1	Constitutive, enhanced by agonist	N.D.	N.D.	Not required for degradation	Wolfe et al., 2007; Chen et al., 2011; Dores et al., 2012;
PAR2	Agonist-induced	c-Cbl	AMSH, UBPY	Lysosomal degradation	Jacob et al., 2005; Hasdemir et al., 2009
Tachykinin receptors
NK₁	Agonist-induced	N.D.	N.D.	Desensitization to sustained substance P stimulation	Cottrell et al., 2006
Thyrotropin-releasing hormone receptor
THR₁	Constitutive	N.D.	N.D.	Biosynthetic turnover, not required for internalization	Cook et al., 2003
Vasopressin and oxytocin receptors
V₂	Agonist-induced	N.D.	N.D.	Arrestin-mediated ubiquitination	Martin et al., 2003
Class B
Glucagon receptors
GIP receptor	Agonist-induced	N.D.	N.D.	Proteasome-dependent	Zhou et al., 2007
Parathyroid hormone receptors
PTH1	Agonist-induced	N.D.	N.D.	Differential ubiquitination and deubiquitination by two ligands	Alonso et al., 2011
Class C
Calcium-sensing receptors
CaS	Constitutive	Dorphin	N.D.	Biosynthetic turnover	Huang et al., 2006
Metabotropic glutamate receptors
mGlu_1a, mGlu₅	Constitutive	Siah1A	N.D.	Via a binding peptide motif (SID) in cytoplasmic tail	Moriyoshi et al., 2004

IUPHAR, International Union of Basic and Clinical Pharmacology; DUB, deubiquitinating enzyme; N.D., not determined; TNF-α, tumor necrosis factor-α.