Table 1:

Summary of the PTM events in Opioid Receptors.

PTM	Receptor	Enzyme	Residue	Occurrence	Role	Ref
Glycosylation	hMOR	Ribophorin I	N40	Constitutive	Regulates levels of MOR at the cell surface; affects agonist-binding. N40D exhibits increased dependence to alcohol and opiates	[39,40,48,50,57]
	hDOR	N.D.	N18; N33	Constitutive	Regulates receptor trafficking.	[56]
		GalNac transferase	S6; S25; S29	Constitutive	Enhances ligand-binding, and modulates cAMP signaling.	[59]
	hKOR	N.D.	N25; N39	Constitutive	Regulates receptor trafficking. Affects agonist-induced phosphorylation.	[37]
Palmitoylation	rMOR	PATs	C170	Constitutive	Facilitates membrane association and modulates subcellular localization.	[15,18,66]
	rDOR	N.D.	C328; C333	Constitutive/Induced	Modulates protein trafficking and subcellular localization. Palmitoylation is increased by agonist treatment.	[67,68]
Phosphorylation	m/rMOR	Src	Y336	Induced	Chronic morphine or etorphine treatment leads to phosphorylation by Src; this switches MOR signaling response from inhibitory to stimulatory.	[80]
		Tyrosine Kinase	Y106; Y166	Induced	DAMGO-mediated tyrosine kinase phosphorylation regulates receptor-G protein coupling efficacy.	[81]
		GRKs	S355; T357; T370; S375; T376; T379	Induced	DAMGO, fentanyl, Met-Enk and etonitazene induce hierarchical phosphorylation of these residues via GRK2/3, facilitating β-arrestin recruitment, MOR internalization, desensitization and tolerance. Morphine induces phosphorylation of S375 and weak phosphorylation of T370, T376 and T379, via GRK5/6.	[69,76,78,85,87–90,100]
		PKC	S363; T370	Constitutive/Induced	Modulates morphine-induced desensitization, and tolerance. PKC inhibition impairs DAMGO-mediated MOR recycling.	[69,77,91,92,101]
		CAMKII	T370; S26	Induced	S266 phosphorylation modulates DAMGO-induced desensitization.	[69,93]
	mDOR	GRK2	T358; S363	Induced	Hierarchical phosphorylation required for clathrin-mediated receptor internalization.	[117,118]
		PKC	S344	Constitutive	Modulates heterologous regulation via β-Arrestin- and clathrin-mediated receptor internalization.	[123]
		Cdk5	T161	Induced	Regulates cell surface expression of DOR and facilitates the formation of DOR-MOR heterodimers.	[151]
	mKOR	GRKs	S356; T357; T363; S369	Induced	U50,488H treatment leads to GRK-mediated phosphorylation, β-arrestin recruitment and internalization.	[119]
		PKC	S356; T357; T363; S369	Constitutive	Modulates agonist independent KOR internalization.	[124]
	mNOP	GRK2/3	S346; S351; T362; S363	Induced	Affects receptor desensitization and internalization.	[116,128]
Ubiquitination	mMOR	N.D.	K98; K100	Induced	Regulates internalization and degradation induced by DAMGO and DADLE treatment.	[98,140,141]
	hDOR	N.D.	N.D.	Induced	Induces receptor internalization and degradation.	[139,142]
	hKOR	N.D.	K63	Induced	Modulates receptor expression.	[144,145].

The list includes (i) the PTM event, (ii) the enzyme responsible for the PTM (iii) the residues involved, (iv) whether the PTM event is agonist induced or constitutive and, (v) the role of the PTM in opioid signaling. N.D., non-described.